Therapeutic agents comprising elastic peptides

ABSTRACT

The present invention provides therapeutic agents and compositions comprising elastic peptides and therapeutic proteins. Such peptides exhibit a flexible, extended conformation. In some embodiments, the therapeutic protein is a GLP-1 receptor agonist (e.g., GLP-1, exendin), insulin, or Factor VII/VIIa, including functional analogs. The present invention further provides encoding polynucleotides, as well as methods of making and using the therapeutic agents. The therapeutic agents have improvements in relation to their use as therapeutics, including, inter alia, one or more of half-life, clearance and/or persistance in the body, solubility, and bioavailability.

PRIORITY

This application is a continuation of U.S. application Ser. No. 12/852,365, filed Aug. 6, 2010, which is a continuation-in-part of U.S. application Ser. No. 12/493,912, filed Jun. 29, 2009, now U.S. Pat. No. 8,178,495, which claims priority to U.S. Provisional Application No. 61/076,221, filed Jun. 27, 2008, each of which is hereby incorporated by reference in its entirety. This application is also a continuation-in-part of U.S. application Ser. No. 12/158,190, which is a U.S. national stage of PCT/US06/048572, filed Dec. 20, 2006, which claims priority to U.S. Provisional Application No. 60/751,896, filed Dec. 20, 2005, each of which is hereby incorporated by reference in its entirety.

GOVERNMENT SUPPORT

This invention was made with Government support under grant number EB00188 and GM-061232 from National Institutes of Health. The US Government has certain rights to this invention.

DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: A computer readable format copy of the Sequence Listing (filename: PHAS_(—)021_(—)01US_SeqList_ST25.txt, date recorded: Sep. 12, 2012, file size 50 kb).

BACKGROUND OF THE INVENTION

Therapeutic proteins or peptides in their native state or when recombinantly produced can be labile molecules exhibiting, inter alia, short periods of serum stability, serum half-life (i.e., circulatory half-life), or limited persistance in the body. Such molecules can also be extremely labile when formulated, such as when formulated in aqueous solutions.

In some instances, polyethylene glycol (PEG) conjugated to a proteinaceous molecule results in a longer-acting, sustained activity of the molecule. PEG attachment, however, can often substantially reduce or even destroy the protein's therapeutic activity. Therapeutic proteins and/or peptides have also been stabilized by fusion to certain proteins that are capable of extending serum half-life. For example, in some instances, therapeutic proteins fused to albumin, transferrin, and antibody fragments exhibit extended serum half-life when compared to the therapeutic protein in the unfused state. See U.S. Pat. No. 7,238,667 (particularly with respect to albumin conjugates), U.S. Pat. No. 7,176,278 (particularly with respect to transferrin conjugates), and U.S. Pat. No. 5,766,883, which are each hereby incorporated by reference in their entireties.

There remains a need in the art for more stable, longer acting, and/or effective proteinaceous molecules.

SUMMARY OF THE INVENTION

The present invention provides therapeutic agents comprising an elastic peptide component and a therapeutic proteinacious component. The elastic peptide component may form a spiral conformation, and/or may have an extended structure relative to an alpha helix. The elastic peptide component may be structurally related to, or derived from, sequences of the elastin protein (elastin-like-peptide or ELP). Such elastic peptide components provide certain therapeutic advantages to the therapeutic agent, such as comparatively better stability, solubility, bioavailability, half-life, persistance, and/or biological action of the therapeutic proteinaceous component. Such properties may be determined, for example, with respect to the therapeutic component's unfused or unconjugated counterpart. In some embodiments, the elastic peptide is an ELP that undergoes a reversible inverse phase transition, which may impart additional practical and/or therapeutic advantages. The invention further provides polynucleotides encoding the therapeutic agents of the invention, as well as methods of treatment or prophylaxis for certain biological conditions.

In a first aspect, the invention provides a therapeutic agent comprising an elastic peptide component and a therapeutic proteinacious component, as well as pharmaceutical compositions containing the same for delivery to a subject or patient in need. The therapeutic component may be selected from active portions of the therapeutic proteins described herein, including those listed in Table 1, or functional analogs thereof. In certain embodiments, the therapeutic component is a GLP-1 receptor agonist, such as GLP-1, exendin-4, or a functional analog thereof. Such therapeutic components are generally effective for, among other things, increasing insulin secretion from the pancreas in a glucose-dependent manner. In other embodiments, the therapeutic component is an insulin or functional analog thereof, which is generally effective for promoting glucose uptake from the blood and storage within cells. In still other embodiments, the therapeutic component is a Factor VII/VIIa or functional analog thereof, which is generally effective for promoting coagulation by activation of Factor X or Factor IX.

The elastic peptide and therapeutic components may be covalently coupled by various means, including chemical coupling (e.g., conjugation) and recombinant fusion technology. In addition, the number of elastic peptide or therapeutic components per molecule, and their respective positions within the molecule, may vary as needed. The therapeutic agent may further include one or more spacer or linker moieties, which in addition to providing the desired functional independence of the elastic peptide and therapeutic components, may optionally provide for additional functionalities, such as a protease-sensitive feature to allow for proteolytic release or activation of the therapeutic component. The therapeutic agent may further include one or more targeting components such as, for example, a peptide or protein to target the therapeutic agent to a particular cell type, e.g., a cancer cell, or to a particular organ.

In a second aspect, the invention provides polynucleotides, such polynucleotides comprising a nucleotide sequence encoding a therapeutic agent of the invention. For example, the nucleotide sequence encodes an elastic peptide fusion with a functional portion of at least one therapeutic protein described herein, including those listed in Table 1 (or functional analog thereof). In certain embodiments, the therapeutic component is a GLP-1 receptor agonist (including GLP-1 and exendin-4), insulin, Factor VII/VIIa, or functional analog thereof. Such polynucleotides may further comprise additional control element(s) operably linked to the nucleotide sequence, such as promoter elements and/or other transcription or expression-related signals. The polynucleotide may be inserted into various vectors, which may be useful for production of the therapeutic agent in host cells, including, for example, bacterial and eukaryotic host cells.

In a third aspect, the invention provides a method for treating or preventing a disease, disorder, or condition in a subject, such as in a mammalian patient, including a human patient. The method comprises administering an effective amount of the therapeutic agent of the invention (or pharmaceutical composition containing the same) to a subject or patient in need thereof. For example, the patient may be in need of an agent having a biological activity or preferred indication listed herein (e.g., in Table 1). In certain embodiments employing a GLP-1 receptor agonist/elastic peptide compound or employing an insulin/elastic peptide compound, the invention provides a method for treating one or more disorders including type 1 or type 2 diabetes, hyperglycemia, and impaired glucose tolerance. In certain other embodiments employing Factor VII/VIIa/elastic peptide compound, the invention provides a method for treating one or more disorders including hemophilia, post-surgical bleeding, anticoagulation-induced bleeding, thrombocytopenia, factor VII deficiency, factor XI deficiency, and intracranial hemorrhage.

Various other aspects, features and embodiments of the invention will be more fully apparent from the following disclosure and appended claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts plasmid pET24d-ELP1-90, encoding an elastin-like-peptide (ELP) component with a 10 unit VPGXG (SEQ ID NO: 3) repeat motif, where guest position X is V, G, and A in the ratio of 5:3:2. This motif is repeated eight times with a final C-terminal 10-unit repeat where X is V, G, A, and W in the ratio 4:3:2:1. This ELP component is represented generally as [(VPGXG)₁₀]₉.

FIG. 2A depicts plasmid pET24d-Ex-4 ELP1-90 encoding an ELP component with VPGXG (SEQ ID NO: 3) repeat motif (as in FIG. 1) cloned in frame with an N-terminal exendin-4 component. FIG. 2B depicts the nucleotide and amino acid sequence of the exendin-4/ELP fusion (SEQ ID NOS: 23 and 24). Primer sequences are indicated (SEQ ID NOS:35-40).

FIG. 3A depicts the nucleotide and amino acid sequence of an exendin-4 construct having an N-terminal Tev (Tobacco Etch Virus cysteine protease) cleavage site (SEQ ID NOS: 25 and 26). Primer sequences are indicated (SEQ ID NOS:38, 41, 42). FIG. 3B also depicts the nucleotide and amino acid sequence of an exendin-4 construct having an N-terminal Tev cleavage site, but with an additional sequence N-terminal to the Tev cleavage site to provide a better target for the protease (SEQ ID NOS: 27 and 28). Primer sequences are indicated (SEQ ID NOS:38, 43,44).

FIG. 4A depicts the nucleotide and amino acid sequence of an exendin-4/ELP fusion as in FIGS. 1-3, but with a DsbA leader sequence to direct secretion into the periplasmic space (SEQ ID NOS: 29 and 30). Primer sequences are indicated (SEQ ID NOS:38, 45, 46). FIG. 4B depicts plasmid pET24d-DsbA-Ex-4 ELP1-90 encoding the fusion of FIG. 4A.

FIG. 5A depicts pPB0868, which encodes GLP-1 (A8G,7-37)ELP1-90. FIG. 5B depicts the nucleotide and amino acid sequence of the encoded fusion protein (SEQ ID NOS: 53 and 54, respectively).

FIG. 6A depicts pPB1022, which encodes GLP-1 (A8G,7-37)ELP1-120. FIG. 6B depicts the nucleotide and amino acid sequence of the encoded fusion protein (SEQ ID NOS: 55 and 56, respectively).

FIG. 7A depicts pPB0788, which encodes Factor VII-ELP1-90. FIG. 7B depicts the nucleotide and amino acid sequence of the encoded fusion protein (SEQ ID NOS: 57 and 58, respectively).

FIG. 8A depicts the nucleotide and amino acid sequence of an insulin (B, C, and A chains) having the ELP component cloned in frame (SEQ ID NOS: 31 and 32). Primer sequences are indicated (SEQ ID NOS: 47 and 48). FIG. 8B depicts plasmid pET24d Insulin-ELP1-90 expressing the insulin/ELP fusion of FIG. 8A.

FIG. 9 is a Western blot for FVII-ELP1-90 from transient transfection of Freestyle HEK293, detected with mouse anti-human FVII monoclonal antibody. Lanes are: (1) culture media; (2) FVII ELP1-90 after purification by phase transition; and FVII control.

FIG. 10 is an SDS-PAGE showing recombinant production of an Exendin-4/ELP4-60 fusion. Lanes are: (M) Protein markers; (1) Exendin-4 ELP4-60 from total lysate; (2) Exendin-4 ELP4-60 from insoluble lysate; (3) Exendin-4 ELP4-60 from soluble lysate; (4) Exendin-4 ELP4-60 from 1st transition (equal volume); (5) Exendin-4 ELP4-60 from 2nd transition (concentrated); (6) Exendin-4 ELP4-60 from 3rd transition (concentrated).

FIG. 11 shows the activation of Factor X by FactorVIIa-ELP1-90, and by Factor VIIa as a comparison. As shown, FactorVIIa-ELP retains full activity.

FIG. 12 shows that Factor VIIa-ELP1-90 has a long PK when administered by i.v. in rats. FactorVIIa has a T₁₂ of about 690 min. as compared to about 45-60 min. for Factor VIIa.

FIG. 13 shows the high in vitro activity of GLP1-ELP and Exendin-4-ELP, when compared to the activity of Exendin peptide.

FIG. 14 shows that GLP1-ELP has a T_(1/2) of about 12.9 hours when administered by i.v. to rats, and a T₁₂ of about 8.6 hours when administered subcutaneously (SQ).

FIG. 15 shows that GLP-1 ELP has a long half-life in rabbits of about 20 hours when administered i.v., and about 24 hours when administered sub-cutaneously.

FIG. 16 shows sustained glycemic control in diabetic mice with GLP-1-ELP.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides therapeutic agents comprising an elastic peptide component and a therapeutic component. The therapeutic component may be selected from Table 1 (e.g., selected from a Therapeutic Protein, or functional portion or functional analog thereof, listed in Table 1), or described herein. In certain embodiments, the therapeutic component is a GLP-1 receptor agonist, such as GLP-1 or exendin-4, or may be insulin, Factor VII/VIIa, or functional analog thereof. The elastic peptide component exhibits a flexibility and freedom of movement that results from its secondary structure characteristics, and overall or substantial lack of a rigid tertiary structure. The elastic peptide components may contain structural units related to, or derived from, sequences of the elastin protein. The elastic peptide provides certain therapeutic advantages, such as comparatively better persistence, stability, solubility, bioavailability, half-life, and/or biological action of the therapeutic component. Such properties may be determined with respect to, for example, an unfused or unconjugated counterpart of the therapeutic component. The invention further provides polynucleotides encoding the therapeutic agents of the invention, as well as methods of treatment or prophylaxis for certain biological conditions, including the preferred indications listed in Table 1, and including diabetes (e.g., Type I and Type II), hyperglycemia, bleeding, hemophilia, and hemorrhage, among others.

For ease of reference in the ensuing discussion, set out below are definitions of some terms appearing in the discussion.

As used herein, the term “therapeutic agent” or “therapeutic component” refers to an agent or component capable of inducing a biological effect in vivo and/or in vitro. The biological effect may be useful for treating and/or preventing a condition, disorder, or disease in a subject or patient.

As used herein, the term “coupled” means that the specified components are either directly covalently bonded to one another (e.g., via chemical conjugation or recombinant fusion technology), or indirectly covalently joined to one another (e.g., via chemical conjugation or recombinant fusion technology) through an intervening moiety or moieties, such as a bridge, spacer, or linker.

As used herein, “half-life” (which generally refers to in vivo half-life or circulatory half-life) is the period of time that is required for a 50% diminution of bioactivity of the active agent to occur. Such term is to be contrasted with “persistence,” which is the overall temporal duration of the active agent in the body, and “rate of clearance” as being a dynamically changing variable that may or may not be correlative with the numerical values of half-life and persistence.

The term “functional analog” refers to a protein that is an active analog (e.g., either chemical or protein analog), derivative, fragment, truncation isoform or the like of a native protein. For example, the functional analog may be a functional analog of a therapeutic protein listed in Table 1, or may be a functional analog of a GLP-1 receptor agonist (e.g., GLP-1, exendin), insulin, or Factor VII/VIIa. A polypeptide is active when it retains some or all of the biological activity of the corresponding native polypeptide, as determined in vivo or in one or more indicative in vitro assays. Exemplary activity assays for certain therapeutic proteins, which are determinative of activity, are listed Table 1. Further, such biological activities and assays for GLP-1 receptor agonists, insulin, and Factor VII/VIIa, which are determinative of whether a given molecule is a “functional analog,” are described in detail elsewhere herein.

As used herein, the term “native,” as used in reference to an amino acid sequence, indicates that the amino acid sequence is found in a naturally-occurring protein.

As used herein, the term “spacer” refers to any moiety, peptide or other chemical entity, that may be interposed between the elastic peptide component and the therapeutic component. For example, the spacer may be a divalent group that is covalently bonded at one terminus to the elastic peptide component, and covalently bonded at the other terminus to the therapeutic component. The therapeutic agents may therefore be open to the inclusion of additional chemical structure that does not preclude the efficacy of the agent for its intended purpose. The spacer may, for example, be a protease-sensitive spacer moiety that is provided to control the pharmacokinetics of the agent, or the spacer may be a protease-resistant moiety.

The therapeutic component and the elastic peptide component may be coupled with one another in any suitable covalent manner, including chemical coupling and recombinant technology, such that the therapeutic agent is efficacious for its intended purpose, and such that the presence of the elastic peptide component enhances the therapeutic component in some functional, therapeutic or physiological aspect. For example, the elastic peptide-coupled therapeutic component may be enhanced in, e.g., its bioavailability, bio-unavailability, therapeutically effective dose, biological action, formulation compatibility, resistance to proteolysis or other degradative modality, solubility, half-life or other measure of persistence in the body subsequent to administration, rate of clearance from the body subsequent to administration, etc. Such enhancement may be determined, for example, in relation to a corresponding unconjugated or unfused counterpart therapeutic (e.g., determined relative to native GLP-1, exendin, insulin, or Factor VII/VIIa, or a therapeutic protein described herein).

In some embodiments, the therapeutic agent of the invention circulates or exists in the body in a soluble form, and escapes filtration by the kidney thereby persisting in the body in an active form. In some embodiments, the therapeutic agents of the invention have a molecular weight of less than the generally recognized cut-off for filtration through the kidney, such as less than about 60 kD, or in some embodiments less than about 55, 50, 45, 40, 30, or 20 kDa, and persist in the body by at least 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, or 100-fold or longer than an uncoupled (e.g., unfused or unconjugated) therapeutic counterpart.

The number of elastic peptide and/or therapeutic components per molecule, and their respective positions within the molecule, may vary among embodiments of the invention. For example, in embodiments where the agent is a recombinant fusion, at least one elastic peptide component may be placed at one or both of the N-terminus and the C-terminus. Where the elastic peptide component is at both the N-terminus and C-terminus of the fusion, the elastic peptide components will flank the therapeutic component. Alternatively, the therapeutic component may be positioned at either or both of the N-terminus and C-terminus. Where the therapeutic component is at both the N-terminus and C-terminus, the therapeutic component will flank the elastic peptide component. In a further embodiment, different therapeutic components are positioned at the N-terminus and C-terminus of the molecule. As discussed in detail herein, in certain embodiments, such therapeutic component(s) may be released by proteolysis of a spacer moiety separating the elastic peptide and therapeutic components. In certain embodiments, the therapeutic component may be inactive in the fused state, and becoming active upon proteolytic release from the elastic peptide component(s). Alternatively, the therapeutic component remains active in the fused state, making proteolytic processing of the therapeutic agent unnecessary for biological activity.

When prepared as recombinant fusions, the therapeutic agent can be prepared by known recombinant expression techniques. For example, to recombinantly produce the therapeutic agent, a nucleic acid sequence encoding the chimeric gene is operatively linked to a suitable promoter sequence such that the nucleic acid sequence encoding such fusion protein will be transcribed and/or translated into the desired fusion protein in the host cells. Preferred promoters are those useful for expression in E. coli, such as the T7 promoter. Any commonly used expression system may be used, including eukaryotic or prokaryotic systems. Specific examples include yeast (e.g., Saccharomyces spp., Pichia spp.), baculovirus, mammalian, and bacterial systems, such as E. coli, and Caulobacter.

The various aspects and embodiments of the invention are described in greater detail in the following sections.

Elastic Peptide Component

The therapeutic agent of the invention may comprise one or more elastic peptide components. The elastic peptide components may comprise or consist of structural peptide units or sequences that are related to, or derived from, the elastin protein (e.g., elastin-like-peptides, or ELPs). Elastic peptides are useful for improving the properties of therapeutic proteins, such as those described herein (e.g., listed in Table 1), including GLP-1 receptor agonists (e.g., GLP-1 or exendin-4), insulin, and Factor VII/VIIa in one or more of bioavailability, therapeutically effective dose, biological action, formulation compatibility, resistance to proteolysis, solubility, half-life or other measure of persistence in the body subsequent to administration, and/or rate of clearance from the body.

The elastic peptide component may be constructed from structural units of from three to about twenty amino acids, or in some embodiments, from four to ten amino acids, such as five or six amino acids. The length of the individual structural units, may vary or may be uniform. In certain embodiments, the elastic peptide component is constructed of a polytetra-, polypenta-, polyhexa-, polyhepta-, polyocta, and polynonapeptide motif of repeating structural units. Exemplary structural units include units defined by SEQ ID NOS: 1-12 (below), which may be employed as repeating structural units, including tandem-repeating units, or may be employed in some combination, to create a peptide component effective for improving the properties of the therapeutic component. Thus, the elastic peptide component may comprise or consist essentially of structural unit(s) selected from SEQ ID NOS: 1-12, as defined below.

The elastic peptide component, comprising such structural units, may be of varying sizes. For example, the elastic peptide component may comprise or consist essentially of from about 10 to about 500 structural units, or in certain embodiments about 15 to about 150 structural units, or in certain embodiments from about 20 to about 100 structural units, or from about 50 to about 90 structural units, including one or a combination of units defined by SEQ ID NOS: 1-12. Thus, the elastic peptide component may have a length of from about 50 to about 2000 amino acid residues, or from about 100 to about 600 amino acid residues, or from about 200 to about 500 amino acid residues, or from about 200 to about 400 amino acid residues.

Elastic polymers (e.g., bioelastic polymers) are known and described in, for example, U.S. Pat. No. 5,520,672 to Urry et al. In general, elastic peptides comprise elastomeric units of bioelastic pentapeptides, tetrapeptides, and/or nonapeptides (e.g., elastin-like peptides). Thus, in some embodiments the elastomeric unit is a pentapeptide, in other embodiments the elastomeric unit is a tetrapeptide, and in still other embodiments the elastomeric unit is a nonapeptide. Bioelastic polymers that may be used to carry out the present invention are set forth in U.S. Pat. No. 4,474,851, which is hereby incorporated by reference in its entirety.

As disclosed in U.S. Pat. No. 4,474,851, elastomeric peptides may have a sequence of regularly appearing β-turns, forming an overall spiral conformation (e.g., a β-spiral, which is a series of regularly repeating β-turns). The spiral structures are more open than the more common α-helix. As a result, the atoms in the peptide backbone have a high freedom of movement (e.g., as compared to the freedom of movement for an α-helix). This is particularly true of librational motions involving peptide moieties. A libration is a torsional oscillation involving simultaneous rotational motions of the two single bonds on each side of a librating moiety. The moiety involved in a libration may be a single peptide bond or several peptide residues. For adequate freedom of motion to exist, it is important, however, that the carbonyl oxygen and the amino hydrogen of the peptide bond not be involved in hydrogen bonding to other parts of the molecule or to other molecules. Otherwise a greater energy barrier to the libration exists and motion will be restricted. Since non-hydrogen-bonded segments having freedom of motion exist in the β-spiral between the points of hydrogen bonding for the β-turns, these segments may be said to be librationally suspended. Librationally suspended segments therefore are a structural feature that exists in certain elastic peptides because of the repeating β-turns with relative infrequent hydrogen bonding. Librationally suspended segments resulting from the β-spiral structure are thought to give rise to elasticity, as will be further discussed.

Another factor leading to the high librational freedom of such molecules is the absence of significant polar interactions between the amino acid residues, either intrachain or interchain, other than a hydrogen bond within the β-turn. The amino acid residues present are mostly hydrophobic or glycine and accordingly do not exert significant forces on one another through space. If a significant number of charged or polar groups were present, electrostatic interactions might limit librational freedom and restrict the number of available states in the relaxed (non-extended) form of the molecules. Polar and charged amino acid residues are not strictly prohibited, however, if their presence does not destroy the elasticity of the eslatic peptide component as a whole. For example, an occasional serine residue is present in naturally occurring tropoelastin without destroying elasticity. Accordingly, hydrophobic amino acid residues and glycines are preferred in forming elastomeric polypeptides of the present type although other amino acids may be present to a some extent.

Although not intending to be bound by theory, the elasticity of polypeptides of the β-turn structure may be caused by thermodynamic drive toward greater entropy. The relaxed state of the β-spiral has a large degree of librational freedom and thus the atoms of the peptide chain can exist in a large number of positions. When the molecules are stretched, the degree of freedom is reduced, particularly for librational motions, and when the tension is released, a thermodynamic driving force toward higher entropy results in reformation of the contracted β-spiral.

Other specific bioelastic polymers that can be used to carry out the present invention are described in U.S. Pat. Nos. 4,132,746, 4,187,852, 4,500,700, 4,589,882, and 4,870,055, each of which are hereby incorporated by reference. Still other examples of bioelastic polymers are set forth in U.S. Pat. No. 6,699,294, U.S. Pat. No. 6,753,311, and U.S. Pat. No. 6,063,061, which are also incorporated by reference in their entirety.

In some embodiments, the β-turn may have the following structure, in the formation of a β-spiral:

wherein R1-R5 represent side chains of amino acid residues 1-5, and m is 0 when the repeating unit is a tetrapeptide or 1 when the repeating unit is a pentapeptide. Nonapeptide repeating units generally consist of sequential tetra- and pentapeptides. The amino acid residues may be hydrophobic amino acid residues, such as those independently selected from alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, and methionine. In many cases, the first amino acid residue of the repeating unit is a residue of valine, leucine, isoleucine or phenylalanine; the second amino acid residue is a residue of proline; the third amino acid residue is a residue of glycine; and the fourth amino acid residue is glycine or a hydrophobic residue such as tryptophan, phenylalanine or tyrosine.

In some embodiments, the elastic peptide component, or in some cases the therapeutic agent, has a size of less than about 65 kDa, or less than about 60 kDa, or less than about 55 kDa, or less than about 50 kDa, or less than about 40 kDa, or less than about 30 or 25 kDa. Three major blood proteins, Human Serum Albumin (HSA), Transferrin (Tf) and IgG, or the Fc portion of IgGs in their glycosylated form, have been exploited to extend the half-lives of proteins and peptides for improved therapeutic use. These molecules are 585, 679 and 480 amino acids in length giving molecular weights of about 66, 77, and ˜75 kDa (including glycosylations), respectively. They are each globular and relatively compact. The half life of these molecules is determined by a number of factors, including charge distribution, rescue of molecules by the neonatal Fc receptor (FcRn) (HSA and Fc) or cycling of Tf through the Tf receptor (TfR), and their size which prevents filtering through the kidney glomerulus. HSA is slightly below the generally regarded cut-off for filtration through the kidney (˜70 kDa) but its charge distribution helps prevent this. It would be anticipated that, in order to achieve half-life extension of the same order as that achieved with HSA, Tf and Fc, a protein of at least this molecular weight range would be required or desirable, i.e. having over 550 amino acids and being over 65 kDa. However, an elastic peptide with a small number of amino acids relative to HSA, Tf and Fc (e.g., in the range of about 300 to 400) and around 30 to 40 kDa may have a half life that matches and/or exceeds that of HSA, Tf, and Fc.

Thus, in some embodiments, the elastic peptide component may have an extended, relatively unstructured (e.g., no definitive tertiary structure due to rotational and/or librational freedom of the peptide backbone) and non-globular form, and thus such molecules may have a large expanded structure in comparison to HSA, Tf and Fc, so as to escape kidney filtration. In such embodiments, the therapeutic agents of the invention have a molecular weight of less than the generally recognized cut-off for filtration through the kidney, such as less than about 60 kD, or in some embodiments less than about 55, 50, 45, 40, 30, or 25 kDa, and persist in the body by at least 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, or 100-fold longer than an uncoupled (e.g., unfused or unconjugated) therapeutic counterpart.

In certain embodiments, the elastic peptide component is an ELP that undergoes a reversible inverse phase transition. ELP components are structurally disordered and highly soluble in water below a transition temperature (Tt), but exhibit a sharp (2-3° C. range) disorder-to-order phase transition when the temperature is raised above the Tt, leading to desolvation and aggregation of the ELP components. For example, the ELP forms insoluble polymers, when reaching sufficient size, which can be readily removed and isolated from solution by centrifugation. Such phase transition is reversible, and isolated insoluble ELPs can be completely resolubilized in buffer solution when the temperature is returned below the Tt of the ELPs. Thus, the therapeutic agents of the invention can, in some embodiments, be separated from other contaminating proteins to high purity using inverse transition cycling procedures, e.g., utilizing the temperature-dependent solubility of the therapeutic agent, or salt addition to the medium. Successive inverse phase transition cycles can be used to obtain a high degree of purity. In addition to temperature and ionic strength, other environmental variables useful for modulating the inverse transition of the therapeutic agents include pH, the addition of inorganic and organic solutes and solvents, side-chain ionization or chemical modification, and pressure.

In certain embodiments, the ELP component does not undergo a reversible inverse phase transition, or does not undergo such a transition at a biologically relevant Tt, and thus the improvements in the biological and/or physiological properties of the molecule (as described elsewhere herein), may be entirely or substantially independent of any phase transition properties. Nevertheless, such phase transition properties may impart additional practical advantages, for example, in relation to the recovery and purification of such molecules.

In certain embodiments, the ELP component(s) may be formed of structural units, including but not limited to:

-   -   (a) the tetrapeptide Val-Pro-Gly-Gly, or VPGG (SEQ ID NO: 1);     -   (b) the tetrapeptide Ile-Pro-Gly-Gly, or IPGG (SEQ ID NO: 2);     -   (c) the pentapeptide Val-Pro-Gly-X-Gly (SEQ ID NO: 3), or VPGXG,         where X is any natural or non-natural amino acid residue, and         where X optionally varies among polymeric or oligomeric repeats;     -   (d) the pentapeptide Ala-Val-Gly-Val-Pro, or AVGVP (SEQ ID NO:         4);     -   (e) the pentapeptide Ile-Pro-Gly-X-Gly, or IPGXG (SEQ ID NO: 5),         where X is any natural or non-natural amino acid residue, and         where X optionally varies among polymeric or oligomeric repeats;     -   (e) the pentapeptide Ile-Pro-Gly-Val-Gly, or IPGVG (SEQ ID NO:         6);     -   (f) the pentapeptide Leu-Pro-Gly-X-Gly, or LPGXG (SEQ ID NO: 7),         where X is any natural or non-natural amino acid residue, and         where X optionally varies among polymeric or oligomeric repeats;     -   (g) the pentapeptide Leu-Pro-Gly-Val-Gly, or LPGVG (SEQ ID NO:         8);     -   (h) the hexapeptide Val-Ala-Pro-Gly-Val-Gly, or VAPGVG (SEQ ID         NO: 9);     -   (I) the octapeptide Gly-Val-Gly-Val-Pro-Gly-Val-Gly, or GVGVPGVG         (SEQ ID NO: 10);     -   (J) the nonapeptide Val-Pro-Gly-Phe-Gly-Val-Gly-Ala-Gly, or         VPGFGVGAG (SEQ ID NO: 11); and     -   (K) the nonapeptides Val-Pro-Gly-Val-Gly-Val-Pro-Gly-Gly, or         VPGVGVPGG (SEQ ID NO: 12).         Such structural units defined by SEQ ID NOS:1-12 may form         structural repeat units, or may be used in combination to form         an ELP component in accordance with the invention. In some         embodiments, the ELP component is formed entirely (or almost         entirely) of one or a combination of (e.g., 2, 3 or 4)         structural units selected from SEQ ID NOS: 1-12. In other         embodiments, at least 75%, or at least 80%, or at least 90% of         the ELP component is formed from one or a combination of         structural units selected from SEQ ID NOS: 1-12, and which may         be present as repeating units.

In certain embodiments, the ELP component(s) contain repeat units, including tandem repeating units, of the pentapeptide Val-Pro-Gly-X-Gly (SEQ ID NO:3), where X is as defined above, and where the percentage of Val-Pro-Gly-X-Gly (SEQ ID NO:3) pentapeptide units taken with respect to the entire ELP component (which may comprise structural units other than VPGXG (SEQ ID NO:3)) is greater than about 75%, or greater than about 85%, or greater than about 95% of the ELP component. The ELP component may contain motifs having a 5 to 15-unit repeat (e.g. about 10-unit repeat) of the pentapeptide of SEQ ID NO: 3, with the guest residue X varying among at least 2 or at least 3 of the units. The guest residues may be independently selected, such as from the amino acids V, I, L, A, G, and W (and may be selected so as to retain a desired inverse phase transition property). The repeat motif itself may be repeated, for example, from about 5 to about 12 times, such as about 8 to 10 times, to create an exemplary ELP component. The ELP component as described in this paragraph may of course be constructed from any one of the structural units defined by SEQ ID NOS: 1-12, or a combination thereof.

In some embodiments, the ELP component may include a β-turn structure. Exemplary peptide sequences suitable for creating a β-turn structure are described in International Patent Application PCT/US96/05186, which is hereby incorporated by reference in its entirety. For example, the fourth residue (X) in the elastin pentapeptide sequence, VPGXG (SEQ ID NO:3), can be altered without eliminating the formation of a β-turn. Alternatively, the ELP component may lack a β-turn, or otherwise have a different conformation and/or folding character.

In certain embodiments, the ELP components include polymeric or oligomeric repeats of the pentapeptide VPGXG (SEQ ID NO: 3), where the guest residue X is any amino acid. X may be a naturally occurring or non-naturally occurring amino acid. In some embodiments, X is selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine and valine. In some embodiments, X is a natural amino acid other than proline or cysteine.

The guest residue X (e.g., with respect to SEQ ID NO: 3, or other ELP structural unit) may be a non-classical (non-genetically encoded) amino acid. Examples of non-classical amino acids include: D-isomers of the common amino acids, 2,4-diaminobutyric acid, α-amino isobutyric acid, A-aminobutyric acid, Abu, 2-amino butyric acid, γ-Abu, ε-Ahx, 6-amino hexanoic acid, Aib, 2-amino isobutyric acid, 3-amino propionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, homocitrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, β-alanine, fluoro-amino acids, designer amino acids such as β-methyl amino acids, Cα-methyl amino acids, Nα-methyl amino acids, and amino acid analogs in general.

Selection of X is independent in each ELP structural unit (e.g., for each structural unit defined herein having a guest residue X). For example, X may be independently selected for each structural unit as an amino acid having a positively charged side chain, an amino acid having a negatively charged side chain, or an amino acid having a neutral side chain, including in some embodiments, a hydrophobic side chain.

In still other embodiments, the ELP component(s) may include polymeric or oligomeric repeats of the pentapeptides VPGXG (SEQ ID NO:3), IPGXG (SEQ ID NO:5) or LPGXG (SEQ ID NO:7), or a combination thereof, where X is as defined above.

In each embodiment, the structural units, or in some cases polymeric or oligomeric repeats, of the elastic peptide sequences may be separated by one or more amino acid residues that do not eliminate the overall effect of the molecule, that is, in imparting certain improvements to the therapeutic component as described. In certain embodiments, such one or more amino acids also do not eliminate or substantially affect the phase transition properties where ELP components are employed (relative to the deletion of such one or more amino acids).

For ELP sequences, in each repeat, X is independently selected. The structure of the resulting ELP components may be described using the notation ELPk [X_(i),Y_(j)-n], where k designates a particular ELP repeat unit, the bracketed capital letters are single letter amino acid codes and their corresponding subscripts designate the relative ratio of each guest residue X in the structural units (where applicable), and n describes the total length of the ELP in number of the structural repeats. For example, ELP1 [V₅A₂G₃-10] designates an ELP component containing 10 repeating units of the pentapeptide VPGXG (SEQ ID NO:3), where X is valine, alanine, and glycine at a relative ratio of 5:2:3; ELP1 [K₁V₂F₁-4] designates an ELP component containing 4 repeating units of the pentapeptide VPGXG (SEQ ID NO:3), where X is lysine, valine, and phenylalanine at a relative ratio of 1:2:1; ELP1 [K₁V₇F₁-9] designates a polypeptide containing 9 repeating units of the pentapeptide VPGXG (SEQ ID NO:3), where X is lysine, valine, and phenylalanine at a relative ratio of 1:7:1; ELP1 [V-5] designates a polypeptide containing 5 repeating units of the pentapeptide VPGXG (SEQ ID NO:3), where X is exclusively valine; ELP1 [V-20] designates a polypeptide containing 20 repeating units of the pentapeptide VPGXG (SEQ ID NO:3), where X is exclusively valine; ELP2 [5] designates a polypeptide containing 5 repeating units of the pentapeptide AVGVP (SEQ ID NO:4); ELP3 [V-5] designates a polypeptide containing 5 repeating units of the pentapeptide IPGXG (SEQ ID NO:5), where X is exclusively valine; ELP4 [V-5] designates a polypeptide containing 5 repeating units of the pentapeptide LPGXG (SEQ ID NO:7), where X is exclusively valine. Such ELP components as described in this paragraph may be used in connection with the present invention to increase the therapeutic properties of the therapeutic component.

Further, the Tt is a function of the hydrophobicity of the guest residue. Thus, by varying the identity of the guest residue(s) and their mole fraction(s), ELPs can be synthesized that exhibit an inverse transition over a 0-100° C. range. Thus, the Tt at a given ELP length may be decreased by incorporating a larger fraction of hydrophobic guest residues in the ELP sequence. Examples of suitable hydrophobic guest residues include valine, leucine, isoleucine, phenyalanine, tryptophan and methionine. Tyrosine, which is moderately hydrophobic, may also be used. Conversely, the Tt may be increased by incorporating residues, such as those selected from the group consisting of: glutamic acid, cysteine, lysine, aspartate, alanine, asparagine, serine, threonine, glycine, arginine, and glutamine; preferably selected from alanine, serine, threonine and glutamic acid.

The ELP component in some embodiments is selected or designed to provide a Tt ranging from about 10 to about 80° C., such as from about 35 to about 60° C., or from about 38 to about 45° C. In some embodiments, the Tt is greater than about 40° C. or greater than about 42° C., or greater than about 45° C., or greater than about 50° C. The transition temperature, in some embodiments, is above the body temperature of the subject or patient (e.g., >37° C.) thereby remaining soluble in vivo, or in other embodiments, the Tt is below the body temperature (e.g., <37° C.) to provide alternative advantages, such as in vivo formation of a drug depot for sustained release of the therapeutic agent.

The Tt of the ELP component can be modified by varying ELP chain length, as the Tt generally increases with decreasing MW. For polypeptides having a molecular weight>100,000, the hydrophobicity scale developed by Urry et al. (PCT/US96/05186, which is hereby incorporated by reference in its entirety) is preferred for predicting the approximate Tt of a specific ELP sequence. However, in some embodiments, ELP component length can be kept relatively small, while maintaining a target Tt, by incorporating a larger fraction of hydrophobic guest residues (e.g., amino acid residues having hydrophobic side chains) in the ELP sequence. For polypeptides having a molecular weight<100,000, the Tt may be predicted or determined by the following quadratic function: Tt=M₀+M₁X+M₂X² where X is the MW of the fusion protein, and M₀=116.21; M₁=−1.7499; M₂=0.010349.

While the Tt of the ELP component, and therefore of the ELP component coupled to a therapeutic component, is affected by the identity and hydrophobicity of the guest residue, X, additional properties of the molecule may also be affected. Such properties include, but are not limited to solubility, bioavailability, persistence, and half-life of the molecule.

As described in PCT/US2007/077767 (published as WO 2008/030968), which is hereby incorporated by reference in its entirety, the ELP-coupled therapeutic component can retain the therapeutic component's biological activity. Additionally, ELPs themselves can exhibit long half-lives. Therefore, ELP components in accordance with the present invention substantially increase (e.g. by greater than 10%, 20%, 30%, 50%, 100%, 200%, 500% or more, in specific embodiments) the half-life of the therapeutic component when conjugated thereto. Such half-life (or in some embodiments persistance or rate of clearance) is determined in comparison to the half-life of the free (unconjugated or unfused) form of the therapeutic component. Furthermore, ELPs may target high blood content organs, when administered in vivo, and thus, can partition in the body, to provide a predetermined desired corporeal distribution among various organs or regions of the body, or a desired selectivity or targeting of a therapeutic agent. In sum, the therapeutic agents contemplated by the invention are administered or generated in vivo as active compositions having extended half-lives (e.g., circulatory half-life), among other potential benefits described herein.

The invention thus provides various agents for therapeutic (in vivo) application, where the therapeutic component is biologically active. Such therapeutic components include, without limitation, growth hormone (GH) particularly human and bovine growth hormone, growth hormone-releasing hormones; interferon including α-. β-, or γ-interferons, etc, interleukin-I; interleukin-II; erythropoietin including α- and β-erythropoietin (EPO), granulocyte colony stimulating factor (GCSF), granulocyte macrophage colony stimulating factor (GM-CSF), anti-agiogenic proteins (e.g., angiostatin, endostatin) PACAP polypeptide (pituitary adenylate cyclase activating polypeptide), vasoactive intestinal peptide (VIP), thyrotrophin releasing hormone (TRH), corticotropin releasing hormone (CRH), vasopressin, arginine vasopressin (AVP), angiotensin, calcitonin, atrial naturetic factor, somatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, insulin, somatotropin, plasminogen tissue activator, coagulation factors including coagulation factors VIII and IX, glucosylceramidase, sargramostim, lenograstin, filgrastin, dornase-α, molgramostim, PEG-L-asparaginase, PEG-adenosine deaminase, hirudin, eptacog-α (human blood coagulation factor VIIa) nerve growth factors, transforming growth factor, epidermal growth factor, basic fibroblast growth factor, VEGF; heparin including low molecular weight heparin, calcitonin; antigens; monoclonal antibodies; vancomycin; desferrioxamine (DFO); parathyroid hormone, an immunogen or antigen, an antibody such as a monoclonal antibody.

Where the therapeutic component is an antibody or antibody sequence, the antibody may be of any isotype, including IgG, IgM, IgA, IgD, and IgE. Where the antibody is IgG, the subtype may be IgG1, IgG2, IgG3, or IgG4. The antibody sequence may be humanized or chimeric. The term “antibody” as used herein includes antibody fragments or segments that retain the capability of binding to a target antigen, for example, Fab, F(ab′)2, and Fv fragments, and the corresponding fragments obtained from antibodies other than IgG. Examples of therapeutic antibodies include but are not limited to herceptin, rituxan, campath, gemtuzumab, herceptin, panorex, rituximab, bexxar, edrecolomab, alemtuzumab, mylotrag, IMC-C225, smartin 195, and mitomomab.

The therapeutic component may also be a therapeutic component listed in Table 1 (e.g., full length or functional portions or functional analogs thereof), as well as GLP-1 receptor agonists such as GLP-1 or exendin-4, insulin, or Factor VII/VIIa, and functional analogs thereof. The structure and activity of such therapeutic components are described in detail below. In some forms of the therapeutic agent, the coupling of the therapeutic component to the elastic peptide is effected by direct covalent bonding or indirect (through appropriate spacer groups) bonding (as described elsewhere herein). Further, the therapeutic component(s) and the elastic peptide component(s) can be structurally arranged in any suitable manner involving such direct or indirect covalent bonding, relative to one another.

Glucaqon-Like Peptide (GLP)-1 Receptor Aqonists

In certain embodiments of the invention, the therapeutic agent comprises an ELP component fused or conjugated to a GLP-1 receptor agonist, such as GLP-1, exendin-4, or functional analogs thereof.

Human GLP-1 is a 37 amino acid residue peptide originating from preproglucagon which is synthesized in the L-cells in the distal ileum, in the pancreas, and in the brain. Processing of preproglucagon to give GLP-1 (7-36)amide, GLP-1 (7-37) and GLP-2 occurs mainly in the L-cells. A simple system is used to describe fragments and analogs of this peptide. For example, Gly⁸-GLP-1 (7-37) designates a fragment of GLP-1 formally derived from GLP-1 by deleting the amino acid residues Nos. 1 to 6 and substituting the naturally occurring amino acid residue in position 8 (Ala) by Gly. Similarly, Lys³⁴ (N^(ε)-tetradecanoyl)-GLP-1 (7-37) designates GLP-1 (7-37) wherein the ε-amino group of the Lys residue in position 34 has been tetradecanoylated. Where reference in this text is made to C-terminally extended GLP-1 analogues, the amino acid residue in position 38 is Arg unless otherwise indicated, the optional amino acid residue in position 39 is also Arg unless otherwise indicated and the optional amino acid residue in position 40 is Asp unless otherwise indicated. Also, if a C-terminally extended analogue extends to position 41, 42, 43, 44 or 45, the amino acid sequence of this extension is as in the corresponding sequence in human preproglucagon unless otherwise indicated.

The parent peptide of GLP-1, proglucagon (PG), has several cleavage sites that produce various peptide products dependent on the tissue of origin including glucagon (PG[32-62]) and GLP-1[7-36]NH₂ (PG[72-107]) in the pancreas, and GLP-1[7-37] (PG[78-108]) and GLP-1[7-36]NH₂ (PG [78-107]) in the L cells of the intestine where GLP-1[7-36]NH₂ (78-107 PG) is the major product. The GLP-1 component in accordance with the invention may be any biologically active product or deivative of proglocagon, or functional analog thereof, including: GLP-1 (1-35), GLP-1 (1-36), GLP-1 (1-36)amide, GLP-1 (1-37), GLP-1 (1-38), GLP-1 (1-39), GLP-1 (1-40), GLP-1 (1-41), GLP-1 (7-35), GLP-1 (7-36), GLP-1 (7-36)amide, GLP-1 (7-37), GLP-1 (7-38), GLP-1 (7-39), GLP-1 (7-40) and GLP-1 (7-41), or a analog of the foregoing. Generally, the GLP-1 component in some embodiments may be expressed as GLP-1 (A-B), where A is an integer from 1 to 7 and B is an integer from 38 to 45, optionally with one or more amino acid substitutions as defined below.

As an overview, after processing in the intestinal L-cells, GLP-1 is released into the circulation, most notably in response to a meal. The plasma concentration of GLP-1 rises from a fasting level of approximately 15 pmol/L to a peak postprandial level of 40 pmol/L. For a given rise in plasma glucose concentration, the increase in plasma insulin is approximately threefold greater when glucose is administered orally compared with intravenously (Kreymann et al., 1987, Lancet 2(8571): 1300-4). This alimentary enhancement of insulin release, known as the incretin effect, is primarily humoral and GLP-1 is now thought to be the most potent physiological incretin in humans. GLP-1 mediates insulin production via binding to the GLP-1 receptor, known to be expressed in pancreatic βcells. In addition to the insulinotropic effect, GLP-1 suppresses glucagon secretion, delays gastric emptying (Wettergen et al., 1993, Dig Dis Sci 38: 665-73) and may enhance peripheral glucose disposal (D'Alessio et al., 1994, J. Clin Invest 93: 2293-6).

A combination of actions gives GLP-1 unique therapeutic advantages over other agents currently used to treat non-insulin-dependent diabetes mellitus (NIDDM). First, a single subcutaneous dose of GLP-1 can completely normalize post prandial glucose levels in patients with NIDDM (Gutniak et al., 1994, Diabetes Care 17: 1039-44). This effect may be mediated both by increased insulin release and by a reduction in glucagon secretion. Second, intravenous infusion of GLP-1 can delay postprandial gastric emptying in patients with NIDDM (Williams et al., 1996, J. Clin Endo Metab 81: 327-32). Third, unlike sulphonylureas, the insulinotropic action of GLP-1 is dependent on plasma glucose concentration (Holz et al., 1993, Nature 361:362-5). Thus, the loss of GLP-1-mediated insulin release at low plasma glucose concentration protects against severe hypoglycemia.

When given to healthy subjects, GLP-1 potently influences glycemic levels as well as insulin and glucagon concentrations (Orskov, 1992, Diabetologia 35:701-11), effects which are glucose dependent (Weir et al., 1989, Diabetes 38: 338-342). Moreover, it is also effective in patients with diabetes (Gutniak, M., 1992, N. Engl J Med 226: 1316-22), normalizing blood glucose levels in type 2 diabetic subjects and improving glycemic control in type 1 patients (Nauck et al., 1993, Diabetologia 36: 741-4, Creutzfeldt et al., 1996, Diabetes Care 19:580-6).

GLP-1 is, however, metabolically unstable, having a plasma half-life (t_(1/2)) of only 1-2 minutes in vivo. Moreover, exogenously administered GLP-1 is also rapidly degraded (Deacon et al., 1995, Diabetes 44: 1126-31). This metabolic instability has limited the therapeutic potential of native GLP-1.

GLP-1[7-36]NH₂ has the following amino acid sequence: HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR (SEQ ID NO: 13), which may be employed as the GLP-1 component in accordance with the invention. Alternatively, the GLP-1 component may contain glycine (G) at the second position, giving, for example, the sequence HGEGTFTSDVSSYLEGQAAKEFIAWLVKGR (SEQ ID NO: 17). The GLP-1 component may be a biologically active fragment of GLP-1, for example, as disclosed in US 2007/0041951, which is hereby incorporated by reference in its entirety. Other fragments and modified sequences of GLP-1 are known in the art (U.S. Pat. No. 5,614,492; U.S. Pat. No. 5,545,618; European Patent Application, Publication No. EP 0658568 A1; WO 93/25579, which are hereby incorporated by reference in their entireties). Such fragments and modified sequences may be used in connection with the present invention, as well as those described below.

Certain structural and functional analogs of GLP-1 have been isolated from the venom of the Gila monster lizards (Heloderma suspectum and Heloderma horridum) and have shown clinical utility. Such molecules find use in accordance with the present invention. In particular, exendin-4 is a 39 amino acid residue peptide isolated from the venom of Heloderma suspectum and shares approximately 52% homology with human GLP-1. Exendin-4 is a potent GLP-1 receptor agonist that stimulates insulin release, thereby lowering blood glucose levels. Exendin-4 has the following amino acid sequence: HGEGTFTSDLSKQMEEEAVRLFEWLKNGGPSSGAPPPS (SEQ ID NO: 14). A synthetic version of exendin-4 known as exenatide (marketed as Byetta®) has been approved for the treatment of Type-2 Diabetes. Although exenatide is structurally analogous to native GLP-1, it has a longer half-life after injection.

While exenatide has the ability to lower blood glucose levels on its own, it can also be combined with other medications such as metformin, a thiozolidinedione, a sulfonylureas, and/or insulin to improve glucose control. Exenatide is administered by injection subcutaneously twice per day using a pre-filled pen device. Typical human responses to exenatide include improvements in the initial rapid release of endogenous insulin, an increase in β-cell growth and replication, suppression of pancreatic glucagon release, delayed gastric emptying, and reduced appetite—all of which function to lower blood glucose. Unlike sulfonylureas and meglitinides, exenatide increases insulin synthesis and secretion in the presence of glucose only, thus lessening the risk of hypoglycemia. Despite the therapeutic utility of exenatide, it has certain undesirable traits, including the requirement of twice daily injections, gastrointestional side effects, and similar to native GLP-1, a relatively short half-life (i.e. approximately 2 hr).

Various functional analogs of GLP-1 and exendin-4 are known, and which find use in accordance with the invention. These include liraglutide (Novo Nordisk, WO98/008871), R1583/taspoglutide (Roche, WO00/034331), CJC-1131 (ConjuChem, WO00/069911), ZP-10/AVE0010 (Zealand Pharma, Sanofi-Aventis, WO01/004156), and LY548806 (Eli Lilly, WO03/018516).

Liraglutide, also known as NN2211, is a GLP-1 receptor agonist analog that has been designed for once-daily injection (Harder et al., 2004, Diabetes Care 27: 1915-21). Liraglutide has been tested in patients with type-2 diabetes in a number of studies and has been shown to be effective over a variety of durations. In one study, treatment with liraglutide improved glycemic control, improved β-cell function, and reduced endogenous glucose release in patients with type-2 diabetes after one week of treatment (Degn et al., 2004, Diabetes 53: 1187-94). In a similar study, eight weeks of 0.6-mg liraglutide therapy significantly improved glycemic control without increasing weight in subjects with type 2 diabetes compared with those on placebo (Harder et al., 2004, Diabetes Care 27: 1915-21).

Thus, in certain embodiments, the GLP-1 receptor agonist in accordance with the invention is as described in WO98/008871, which is hereby incorporated by reference in its entirety. The GLP-1 receptor agonist may have at least one lipophilic substituent, in addition to one, two, or more amino acid substitutions with respect to native GLP-1. For example, the lipophilic substituent may be an acyl group selected from CH₃(CH₂)_(n)CO—, wherein n is an integer from 4 to 38, such as an integer from 4 to 24. The lipophilic substituent may be an acyl group of a straight-chain or branched alkyl or fatty acid (for example, as described in WO98/008871, which description is hereby incorporated by reference).

In certain embodiments, the GLP-1 component is Arg²⁶-GLP-1 (7-37), Arg³⁴-GLP-1(7-37), Lys³⁶-GLP-1 (7-37), Arg^(26,34)Lys³⁶-GLP-1 (7-37), Arg^(26,34)Lys³⁸-GLP-I (7-38), Arg^(28,34) Lys³⁹-GLP-1 (7-39), Arg^(26,34)Lys⁴⁰-GLP-1 (7-40), Arg²⁶Lys³⁶-GLP-1(7-37), Arg³⁴Lys³⁶-GLP-1(7-37), Arg²⁶Lys³⁹-GLP-1(7-39), Arg³⁴Lys⁴⁰-GLP-1(7-40), Arg^(26,34)Lys^(36,39)-GLP-I (7-39), Arg^(26,34)Lys^(36,40)-GLP-1 (7-40), Gly⁸Arg²⁶-GLP-1(7-37); Gly⁸Arg³⁴-GLP-1(7-37); Gly⁸Lys³⁸-GLP-1(7-37); Gly⁸Arg^(26,34)Lys³⁶-GLP-1(7-37), Gly⁸Arg^(26,34)Lys^(39-GLP-)1(7-39), Gly⁸Arg^(26,34)Lys⁴⁰-GLP-1(7-40), Gly⁸Arg²⁶Lys³⁶-GLP-1(7-37), Gly⁸Arg³⁴Lys³⁶-GLP-1(7-37), Gly⁸Arg²⁶Lys³⁹-GLP-1(7-39); Gly⁸Arg³⁴Lys⁴⁰-GLP-1(7-40), Gly⁸Arg^(28,34)Lys^(36,39)-GLP-1(7-39) and Gly⁸Arg^(26,34)Lys^(35,40)GLP-1(7-40), each optionally having a lipophilic substituent. For example, the GLP-1 receptor agonist may have the sequence/structure Arg³⁴Lys²⁶-(N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-I (7-37).

Taspoglutide, also known as R1583 or BIM 51077, is a GLP-1 receptor agonist that has been shown to improve glycemic control and lower body weight in subjects with type 2 diabetes mellitus treated with metformin (Abstract No. A-1604, Jun. 7, 2008, 68th American Diabetes Association Meeting, San Francisco, Calif.).

Thus, in certain embodiments, the GLP-1 receptor agonist is as described in WO00/034331, which is hereby incorporated by reference in its entirety. In certain exemplary embodiments, the GLP-1 receptor agonist has the sequence [Aib^(8,35)]hGLP-1(7-36)NH₂ (e.g. taspoglutide), wherein Aib is alpha-aminoisobutyric acid.

CJC-1131 is a GLP-1 analog that consists of a DPP-IV-resistant form of GLP-1 joined to a reactive chemical linker group that allows GLP-1 to form a covalent and irreversible bond with serum albumin following subcutaneous injection (Kim et al., 2003, Diabetes 52: 751-9). In a 12-week, randomized, double-blind, placebo-controlled multicenter study, CJC-1131 and metformin treatment was effective in reducing fasting blood glucose levels in type 2 diabetes patients (Ratner et al., Abstract No. 10-OR, Jun. 10-14th, 2005, 65th American Diabetes Association Meeting, San Francisco, Calif.).

Thus, in certain embodiments, the GLP-1 receptor agonist is as described in WO00/069911, which is hereby incorporated by reference in its entirety. In some embodiments, the GLP-1 receptor agonist is modified with a reactive group which reacts with amino groups, hydroxyl groups or thiol groups on blood components to form a stable covalent bond. In certain embodiments, the GLP-1 receptor agonist is modified with a reactive group selected from the group consisting of succinimidyl and maleimido groups. In certain exemplary embodiments, the GLP-1 receptor agonist has the sequence/structure: D-Ala⁸Lys³⁷-(2-(2-(2-maleimidopropionamido(ethoxy)ethoxy)acetamide))-GLP-1(7-37) (e.g. CJC-1131).

AVE0010, also known as ZP-10, is a GLP-1 receptor agonist that may be employed in connection with the invention. In a recent double-blind study, patients treated with once daily dosing of AVE0010 demonstrated significant reductions in HbA1c levels (Ratner et al., Abstract No. 433-P, 68th American Diabetes Association Meeting, San Francisco, Calif.). At the conclusion of the study, the percentages of patients with HbA1c<7% ranged from 47-69% for once daily dosing compared to 32% for placebo. In addition, AVE0010 treated patients showed dose-dependent reductions in weight and post-prandial plasma glucose.

Thus, in certain embodiments, the GLP-1 receptor agonist is as described in WO01/004156, which is hereby incorporated by reference in its entirety. For example, the GLP-1 receptor agonist may have the sequence: HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK-NH2 (SEQ ID NO: 18) (e.g. AVE0010).

LY548806 is a GLP-1 derivative designed to be resistant to proteolysis by dipeptidase-peptidyl IV (DPP-IV) (Jackson et al., Abstract No. 562, Jun. 10-14th, 2005, 65th American Diabetes Association Meeting, San Francisco, Calif.). In an animal model of hyperglycemia, LY548806 has been shown to produce a significant lowering of blood glucose levels during the hyperglycemic phase (Saha et al., 2006, J. Pharm. Exp. Ther. 316: 1159-64). Moreover, LY548806 was shown to produce a significant increase in insulin levels consistent with its known mechanism of action, namely stimulation of insulin release in the presence of hyperglycemia.

Thus, in certain embodiments, the GLP-1 receptor agonist is as described in WO03/018516, which is hereby incorporated by reference in its entirety. In some embodiments, the therapeutic agents of the present invention comprise GLP-1 analogs wherein the backbone for such analogs or fragments contains an amino acid other than alanine at position 8 (position 8 analogs). The backbone may also include L-histidine, D-histidine, or modified forms of histidine such as desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, homohistidine, α-fluoromethyl-histidine, or α-methyl-histidine at position 7. In some embodiments, these position 8 analogs may contain one or more additional changes at positions 12, 16, 18, 19, 20, 22, 25, 27, 30, 33, and 37 compared to the corresponding amino acid of native GLP-1. In other embodiments, these position 8 analogs may contain one or more additional changes at positions 16, 18, 22, 25 and 33 compared to the corresponding amino acid of native GLP-1. In certain exemplary embodiments, the GLP-1 receptor agonist has the sequence: HVEGTFTSDVSSYLEEQAAKEFIAWLIKGRG-OH (SEQ ID NO: 19) (e.g. LY548806).

Thus, the present invention provides therapeutic agents comprising an elastic peptide (e.g., an ELP) and a GLP-1 receptor agonist. For example, in certain embodiments, the GLP-1 receptor agonist is GLP-1 (SEQ ID NO:13, 17, or 59) or a functional analog thereof. In other embodiments, the GLP-1 receptor agonist is exendin-4 (SEQ ID NO:14) or a functional analog thereof. Such functional analogs of GLP-1 or exendin-4 include functional fragments truncated at the C-terminus by from 1 to 10 amino acids, including by 1, 2, 3, or up to about 5 amino acids (with respect to SEQ ID NOS: 13, 14, 17, or 59). Such functional analogs may contain from 1 to 10 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the native sequence (e.g., SEQ ID NOS 13, 14, and 59), and in each case retaining the activity of the peptide. For example, the functional analog of GLP-1 or exendin-4 may have from 1 to about 3, 4, or 5 insertions, deletions and/or substitutions (collectively) with respect to SEQ ID NOS: 13, 59 and 14, and in each case retaining the activity of the peptide. Such activity may be confirmed or assayed using any available assay, including those described herein. In these or other embodiments, the GLP-1 receptor agonist component has at least about 50%, 75%, 80%, 85%, 90%, or 95% identity with the native sequence (SEQ ID NOS: 13, 59, and 14). The determination of sequence identity between two sequences (e.g., between a native sequence and a functional analog) can be accomplished using any alignment tool, including Tatusova et al., Blast 2 sequences—a new tool for comparing protein and nucleotide sequences, FEMS Microbiol Lett. 174:247-250 (1999). Such functional analogs may further comprise additional chemical modifications, such as those described in this section and/or others known in the art.

In certain embodiments, the GLP1-ELP fusion has a sequence exemplified herein as SEQ ID NOS: 54 and 56. When processed, the mature form of such fusion protein will begin with the His⁷ of GLP.

In another aspect, the present invention provides methods for the treatment or prevention of type 2 diabetes, impaired glucose tolerance, type 1 diabetes, hyperglycemia, obesity, binge eating, bulimia, hypertension, syndrome X, dyslipidemia, cognitive disorders, atheroschlerosis, non-fatty liver disease, myocardial infarction, coronary heart disease and other cardiovascular disorders. The method comprises administering the therapeutic agent comprising the elastin-like peptide (ELP) and the GLP-1 receptor agonist (as described above) to a patient in need of such treatment. In these or other embodiments, the present invention provides methods for decreasing food intake, decreasing β-cell apoptosis, increasing β-cell function and β-cell mass, and/or for restoring glucose sensitivity to β-cells. Generally, the patient may be a human or non-human animal patient (e.g., dog, cat, cow, or horse). Preferably, the patient is human.

The treatment with a ELP/GLP-1 receptor agonist compound according to the present invention may also be combined with one or more pharmacologically active substances, e.g. selected from antidiabetic agents, antiobesity agents, appetite regulating agents, antihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity. In the present context, the expression “antidiabetic agent” includes compounds for the treatment and/or prophylaxis of insulin resistance and diseases wherein insulin resistance is the pathophysiological mechanism.

The ability of a GLP-1 or exendin-4 analog, or an GLP-1 receptor agonist/elastic peptide compound, to bind the GLP-1 receptor may be determined by standard methods, for example, by receptor-binding activity screening procedures which involve providing appropriate cells that express the GLP-1 receptor on their surface, for example, insulinoma cell lines such as RINmSF cells or INS-1 cells. In addition to measuring specific binding of tracer to membrane using radioimmunoassay methods, cAMP activity or glucose dependent insulin production can also be measured. In one method, a polynucleotide encoding the GLP-1 receptor is employed to transfect cells to thereby express the GLP-1 receptor protein. Thus, these methods may be employed for testing or confirming whether a suspected GLP-1 receptor agonist is active. An exemplary assay is described in greater detail herein.

In addition, known methods can be used to measure or predict the level of biologically activity of a GLP-1 receptor agonist or GLP-1 receptor agonist/elastic peptide in vivo (See e.g. Siegel, et al., 1999, Regul Pept 79(2-3): 93-102). In particular, GLP-1 receptor agonists or GLP-1 receptor agonist/elastic peptide compounds can be assessed for their ability to induce the production of insulin in vivo using a variety of known assays for measuring GLP-1 activity. For example, a GLP-1 receptor agonist/elastic peptide compound can be introduced into a cell, such as an immortalized β-cell, and the resulting cell can be contacted with glucose. If the cell produces insulin in response to the glucose, then the modified GLP-1 is generally considered biologically active in vivo (Fehmann et al., 1992, Endocrinology 130: 159-166). An exemplary assay is described in greater detail herein.

The ability of an GLP-1 receptor agonist/elastic peptide compound to enhance β-cell proliferation, inhibit β-cell apoptosis, and regulate islet growth may also be measured using known assays. Pancreatic β-cell proliferation may be assessed by ³H-tymidine or BrdU incorporation assays (See e.g. Buteau et al., 2003, Diabetes 52: 124-32), wherein pancreatic β-cells such as INS(832/13) cells are contacted with a GLP-1 receptor agonist/elastic peptide compound and analyzed for increases in ³H-thymidine or BrdU incorporation. The antiapoptotic activity of a GLP-1 receptor agonist/elastic peptide compound can be measured in cultured insulin-secreting cells and/or in animal models where diabetes occurs as a consequence of an excessive rate of beta-cell apoptosis (See e.g. Bulotta et al., 2004, Cell Biochem Biophys 40(3 suppl): 65-78).

In addition to GLP-1, other peptides of this family, such as those derived from processing of the pro-glucagon gene, such as GLP-2, GIP, and oxyntomodulin, could be conjugated or fused to the elastic peptide component (as described herein) to enhance the therapeutic potential.

Insulin

In other embodiments, the present invention provides a therapeutic agent comprising an elastin peptide component coupled to insulin (e.g., via fusion or conjugation). Insulin injections, e.g. of human insulin, can be used to treat diabetes. The insulin-making cells of the body are called β-cells, and they are found in the pancreas gland. These cells clump together to form the “islets of Langerhans”, named for the German medical student who described them.

The synthesis of insulin begins at the translation of the insulin gene, which resides on chromosome 11. During translation, two introns are spliced out of the mRNA product, which encodes a protein of 110 amino acids in length. This primary translation product is called preproinsulin and is inactive. It contains a signal peptide of 24 amino acids in length, which is required for the protein to cross the cell membrane.

Once the preproinsulin reaches the endoplasmic reticulum, a protease cleaves off the signal peptide to create proinsulin. Proinsulin consists of three domains: an amino-terminal B chain, a carboxyl-terminal A chain, and a connecting peptide in the middle known as the C-peptide. Insulin is composed of two chains of amino acids named chain A (21 amino acids-GIVEQCCASVCSLYQLENYCN) (SEQ ID NO: 15) and chain B (30 amino acids FVNQHLCGSHLVEALYLVCGERGFFYTPKA) (SEQ ID NO: 16) that are linked together by two disulfide bridges. There is a 3rd disulfide bridge within the A chain that links the 6th and 11th residues of the A chain together. In most species, the length and amino acid compositions of chains A and B are similar, and the positions of the three disulfide bonds are highly conserved. For this reason, pig insulin can replace deficient human insulin levels in diabetes patients. Today, porcine insulin has largely been replaced by the mass production of human proinsulin by bacteria (recombinant insulin).

Insulin molecules have a tendency to form dimers in solution, and in the presence of zinc ions, insulin dimers associate into hexamers. Whereas monomers of insulin readily diffuse through the blood and have a rapid effect, hexamers diffuse slowly and have a delayed onset of action. In the design of recombinant insulin, the structure of insulin can be modified in a way that reduces the tendency of the insulin molecule to form dimers and hexamers but that does not interrupt binding to the insulin receptor. In this way, a range of preparations are made, varying from short acting to long acting.

Within the endoplasmic reticulum, proinsulin is exposed to several specific peptidases that remove the C-peptide and generate the mature and active form of insulin. In the Golgi apparatus, insulin and free C-peptide are packaged into secretory granules, which accumulate in the cytoplasm of the β-cells. Exocytosis of the granules is triggered by the entry of glucose into the beta cells. The secretion of insulin has a broad impact on metabolism.

There are two phases of insulin release in response to a rise in glucose. The first is an immediate release of insulin. This is attributable to the release of preformed insulin, which is stored in secretory granules. After a short delay, there is a second, more prolonged release of newly synthesized insulin.

Once released, insulin is active for a only a brief time before it is degraded by enzymes. Insulinase found in the liver and kidneys breaks down insulin circulating in the plasma, and as a result, insulin has a half-life of only about 6 minutes. This short duration of action results in rapid changes in the circulating levels of insulin.

Insulin analogs have been developed with improved therapeutic properties (Owens et al., 2001, Lancet 358: 739-46; Vajo et al., 2001, Endocr Rev 22: 706-17), and such analogs may be employed in connection with the present invention. Various strategies, including elongation of the COOH-terminal end of the insulin B-chain and engineering of fatty acid-acylated insulins with substantial affinity for albumin are used to generate longer-acting insulin analogs. However, in vivo treatments with available longer-acting insulin compounds still result in a high frequency of hypo- and hyperglycemic excursions and modest reduction in HbA_(1c). Accordingly, development of a truly long-acting and stable human insulin analog still remains an important task.

Functional analogs of insulin that may be employed in accordance with the invention include rapid acting analogs such as lispro, aspart and glulisine, which are absorbed rapidly (<30 minutes) after subcutaneous injection, peak at one hour, and have a relatively short duration of action (3 to 4 hours). In addition, two long acting insulin analogs have been developed: glargine and detemir, and which may be employed in connection with the invention. The long acting insulin analogs have an onset of action of approximately two hours and reach a plateau of biological action at 4 to 6 hours, and may last up to 24 hours.

Thus, in one embodiment, the insulin component may contain the A and/or B chain of lispro (also known as Humalog, Eli Lilly). Insulin lispro differs from human insulin by the substitution of proline with lysine at position 28 and the substitution of lysine with proline at position 29 of the insulin B chain. Although these modifications do not alter receptor binding, they help to block the formation of insulin dimers and hexamers, allowing for larger amounts of active monomeric insulin to be available for postprandial injections.

In another embodiment, the insulin may contain an A and/or B chain of aspart (also known as Novolog, Novo Nordisk). Insulin aspart is designed with the single replacement of the amino acid proline by aspartic acid at position 28 of the human insulin B chain. This modification helps block the formation for insulin hexamers, creating a faster acting insulin.

In yet another embodiment, the insulin may contain an A and/or B chain of glulisine (also known as Apidra, Sanofi-Aventis). Insulin glulisine is a short acting analog created by substitution of asparagine at position 3 by lysine and lysine at position 29 by glutamine of human insulin B chain. Insulin glulisine has more rapid onset of action and shorter duration of action compared to regular human insulin.

In another embodiment, the insulin may contain an A and/or B chain of glargine (also known as Lantus, Sanofi-Aventis). Insulin glargine differs from human insulin in that the amino acid asparagine at position 21 of the A chain is replaced by glycine and two arginines are added to the C-terminus of the B-chain. Compared with bedtime neutral protamine Hagedorn (NPH) insulin (an intermediate acting insulin), insulin glargine is associated with less nocturnal hypoglycemia in patients with type 2 diabetes.

In yet another embodiment, the insulin may contain an A and/or B chain from detemir (also known as Levemir, Novo Nordisk). Insulin detemir is a soluble (at neutral pH) long-acting insulin analog, in which the amino acid threonine at B30 is removed and a 14-carbon, myristoyl fatty acid is acetylated to the epsilon-amino group of LysB29. After subcutaneous injection, detemir dissociates, thereby exposing the free fatty acid which enables reversible binding to albumin molecules. So at steady state, the concentration of free unbound insulin is greatly reduced resulting in stable plasma glucose levels.

In some embodiments, the insulin may be a single-chain insulin analog (SIA) (e.g. as described in 6,630,438 and WO08/019,368, which are hereby incorporated by reference in their entirety). Single-chain insulin analogs encompass a group of structurally-related proteins wherein the A and B chains are covalently linked by a polypeptide linker. The polypeptide linker connects the C-terminus of the B chain to the N-terminus of the A chain. The linker may be of any length so long as the linker provides the structural conformation necessary for the SIA to have a glucose uptake and insulin receptor binding effect. In some embodiments, the linker is about 5-18 amino acids in length. In other embodiments, the linker is about 9-15 amino acids in length. In certain embodiments, the linker is about 12 amino acids long. In certain exemplary embodiments, the linker has the sequence KDDNPNLPRLVR (SEQ ID NO.: 20) or GAGSSSRRAPQT (SEQ ID NO.: 21). However, it should be understood that many variations of this sequence are possible such as in the length (both addition and deletion) and substitutions of amino acids without substantially compromising the effectiveness of the produced SIA in glucose uptake and insulin receptor binding activities. For example, several different amino acid residues may be added or removed from either end without substantially decreasing the activity of the produced SIA.

An exemplary single-chain insulin analog currently in clinical development is albulin (Duttaroy et al., 2005, Diabetes 54: 251-8). Albulin can be produced in yeast or in mammalian cells. It consists of the B and A chain of human insulin (100% identity to native human insulin) linked together by a dodecapeptide linker and fused to the NH₂ terminals of the native human serum albumin. For expression and purification of albulin, Duttaroy et al. constructed a synthetic gene construct encoding a single-chain insulin containing the B- and A-chain of mature human insulin linked together by a dodecapeptide linker using four overlapping primers and PCR amplification. The resulting PCR product was ligated in-frame between the signal peptide of human serum albumin (HSA) and the NH₂ terminus of mature HSA, contained within a pSAC35 vector for expression in yeast. In accordance with the present invention, the HSA component of abulin may be replaced with an ELP component as described herein.

Thus, in one aspect, the present invention provides therapeutic agents comprising an elastic peptide and an insulin or functional analog thereof. For example, in certain embodiments, the insulin is a mammalian insulin, such as human insulin or porcine insulin. In accordance with the invention, the elastic peptide component may be coupled (e.g., via recombinant fusion or chemical conjugation) to the insulin A chain, or B chain, or both. The insulin may comprise each of chains A, B, and C (SEQ ID NOS: 51 and 52), or may contain a processed form, containing only chains A and B. In some embodiments, chains A and B are connected by a short linking peptide, to create a single chain insulin. The insulin may be a functional analog of human insulin, including functional fragments truncated at the N-terminus and/or C-terminus (of either or both of chains A and B) by from 1 to 10 amino acids, including by 1, 2, 3, or about 5 amino acids. Functional analogs may contain from 1 to 10 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the native sequence (e.g., SEQ ID NOS 15 and 16), and in each case retaining the activity of the peptide. For example, functional analogs may have 1, 2, 3, 4, or 5 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the native sequence (which may contain chains A and B, or chains A, B, and C). Such activity may be confirmed or assayed using any available assay, including those described herein. In these or other embodiments, the insulin component has at least about 75%, 80%, 85%, 90%, 95%, or 98% identity with each of the native sequences for chains A and B (SEQ ID NOS:15 and 16). The determination of sequence identity between two sequences (e.g., between a native sequence and a functional analog) can be accomplished using any alignment tool, including Tatusova et al., Blast 2 sequences—a new tool for comparing protein and nucleotide sequences, FEMS Microbiol Lett. 174:247-250 (1999). The insulin component may contain additional chemical modifications known in the art.

In another aspect, the present invention provides methods for the treatment or prevention of diabetes, including type I and II diabetes. The method comprises administering an effective amount of the therapeutic agent comprising an elastic peptide (e.g., ELP) component and an insulin (or functional analog thereof) component to a patient in need thereof. Generally, the patient may be a human or non-human animal (e.g., dog, cat, cow, or horse) patient. Preferably, the patient is human.

To characterize the in vitro binding properties of an insulin analog or an elastic peptide-containing insulin analog, competition binding assays may be performed in various cell lines that express the insulin receptor (Jehle et al., 1996, Diabetologia 39: 421-432). For example, competition binding assays using CHO cells overexpressing the human insulin receptor may be employed. Insulin can also bind to the IGF-1 receptor with a lower affinity than the insulin receptor. To determine the binding affinity of an ELP-containing insulin analog, a competition binding assay can be performed using ¹²⁵I-labeled IGF-1 in L6 cells.

The activities of insulin include stimulation of peripheral glucose disposal and inhibition of hepatic glucose production. The ability of an elastic peptide-containing insulin analog to mediate these biological activities can be assayed in vitro using known methodologies. For example, the effect of an elastic peptide-containing analog on glucose uptake in 3T3-L1 adipocytes can be measured and compared with that of insulin. Pretreatment of the cells with a biologically active analog will generally produce a dose-dependent increase in 2-deoxyglucose uptake. The ability of an elastic peptide-containing insulin analog to regulate glucose production may be measured in any number of cells types, for example, H4IIIe hepatoma cells. In this assay, pretreatment with a biologically active analog will generally result in a dose-dependent inhibition of the amount of glucose released.

Factor VII (VIIa)

In certain embodiments, the invention provides therapeutic agents comprising an elastic peptide component coupled (e.g., via fusion or conjugation) to a Factor VII/VIIa. Coagulation is the biological process of blood clot formation involving many different serine proteases as well as their essential cofactors and inhibitors. It is initiated by exposure of Factor VII (FVII) and Factor VIIa (FVIIa) to its membrane bound cofactor, tissue factor (TF), resulting in production of Factor Xa (FXa) and more FVIIa. The process is propagated upon production of Factor IXa (FIXa) and additional FXa that, upon binding with their respective cofactors FVIIIa and FVa, form platelet bound complexes, ultimately resulting in the formation of thrombin and a fibrin clot. Thrombin also serves to further amplify coagulation by activation of cofactors such as FV and FVII and zymogens such as Factor XI. Moreover, thrombin activates platelets leading to platelet aggregation, which is necessary for the formation of a hemostatic plug.

Factor VII circulates in the blood in a zymogen form, and is converted to its active form, Factor VIIa, by either factor IXa, factor Xa, factor XIIa, or thrombin by minor proteolysis. Factor VIIa is a two-chain, 50 kilodalton (kDa) plasma serine protease. The active form of the enzyme comprises a heavy chain (254 amino acid residues) containing a catalytic domain and a light chain (152 residues) containing 2 epidermal growth factor (EGF)-like domains. The mature factor VII/VIIa that circulates in plasma is composed of 406 amino acid residues (SEQ ID NO: 33). The light and heavy chains are held together by a disulfide bond.

As noted above, Factor VIIa is generated by proteolysis of a single peptide bond from its single chain zymogen, Factor VII, which is present at approximately 0.5 μg/ml in plasma. The conversion of zymogen Factor VII into the activated two-chain molecule occurs by cleavage of an internal peptide bond. In human Factor VII, the cleavage site is at Arg152-Ile153 (Hagen et al., 1986, PNAS USA 83: 2412-6).

“Factor VII/VIIa” as used in this application means a product consisting of either the unactivated form (factor VII) or the activated form (factor VIIa) or mixtures thereof. “Factor VII/VIIa” within the above definition includes proteins that have an amino acid sequence of native human factor VII/VIIa. It also includes proteins with a slightly modified amino acid sequence, for instance, a modified N-terminal end including N-terminal amino acid deletions or additions so long as those proteins substantially retain the activity of factor VIIa. “Factor VII” within the above definition also includes natural allelic variations that may exist and occur from one individual to another. Also, degree and location of glycosylation or other post-translation modifications may vary depending on the chosen host cells and the nature of the host cellular environment.

In the presence of calcium ions, Factor VIIa binds with high affinity to TF. TF is a 263 amino acid residue glycoprotein composed of a 219 residue extracellular domain, a single transmembrane domain, and a short cytoplasmic domain (Morrissey et al., 1987, Cell 50: 129-35). The TF extracellular domain is composed of two fibronectin type III domains of about 105 amino acids each. The binding of FVIIa is mediated entirely by the TF extracellular domain (Muller et al., 1994, Biochem. 33:10864-70). Residues in the area of amino acids 16-26 and 129-147 contribute to the binding of FVIIa as well as the coagulant function of the molecule. Residues Lys20, Trp45, Asp58, Tyr94, and Phe140 make a large contribution (1 kcal/mol) to the free energy (ΔG) of binding to FVIIa.

TF is expressed constitutively on cells separated from plasma by the vascular endothelium. Its expression on endothelial cells and monocytes is induced by exposure to inflammatory cytokines or bacterial lipopolysaccharides (Drake et al., 1989, J. Cell Biol. 109: 389). Upon tissue injury, the exposed extracellular domain of TF forms a high affinity, calcium dependent complex with FVII. Once bound to TF, FVII can be activated by peptide bond cleavage to yield serine protease FVIIa. The enzyme that catalyzes this step in vivo has not been elucidated, but in vitro FXa, thrombin, TF:FVIIa and FIXa can catalyze this cleavage. FVIIa has only weak activity upon its physiological substrates FX and FIX whereas the TF:FVIIa complex rapidly activates FX and FIX.

The TF:FVIIa complex constitutes the primary initiator of the extrinsic pathway of blood coagulation. The complex initiates the extrinsic pathway by activation of FX to Factor Xa (FXa), FIX to Factor IXa (FIXa), and additional FVII to FVIIa. The action of TF:FVIIa leads ultimately to the conversion of prothrombin to thrombin, which carries out many biological functions. Among the most important activities of thrombin is the conversion of fibrinogen to fibrin, which polymerizes to form a clot. The TF:FVIIa complex also participates as a secondary factor in extending the physiological effects of the contact activation system.

The initiation and subsequent regulation of coagulation is complex, since maintenance of hemostasis is crucial for survival. There is an exquisite balance between hemostasis (normal clot formation and dissolution) and thrombosis (pathogenic clot formation). Serious clinical conditions involving aberrations in coagulation include deep vein thrombosis, myocardial infarction, pulmonary embolism, stroke and disseminated intravascular coagulation (in sepsis). There are also many bleeding coagulopathies where there is insufficient clot formation. These include hemophilia A (FVIII deficiency) or hemophilia B (FIX deficiency), where procoagulant therapy is required. The challenge in this therapeutic area is to operate in the narrow window between too much and too little coagulation.

The use of exogenous FVIIa as a therapeutic agent has been shown to induce hemostasis in patients with hemophilia A and B (Hedner, 2001, Seminars Hematol. 38 (suppl. 12): 43-7; Hedner, 2004, Seminars Hematol. 41 (suppl. 1): 35-9). It also has been used to treat bleeding in patients with liver disease, anticoagulation-induced bleeding, surgery, thrombocytopenia, thrombasthenia, Bemard-Soulier syndrome, von Willebrand disease, and other bleeding disorders (See e.g. Roberts et al., 2004, Blood 104: 3858-64).

Commercial preparations of human recombinant FVIIa are sold as NovoSeven.™ NovoSeven™ is indicated for the treatment of bleeding episodes in hemophilia A or B patients and is the only recombinant FVIIa effective for bleeding episodes currently available. A circulating recombinant FVIIa half-life of 2.3 hours was reported in “Summary Basis for Approval for NovoSeven™” FDA reference number 96-0597. Moreover, the half-life of recombinant FVIIa is shorter in pediatric patients (˜1.3 hours), suggesting that higher doses of recombinaint FVIIa may be required in this population (Roberts et al., 2004, Blood 104: 3858-64). Accordingly, relatively high doses and frequent administration are necessary to reach and sustain the desired therapeutic or prophylactic effect. As a consequence, adequate dose regulation is difficult to obtain and the need of frequent intravenous administrations imposes restrictions on the patient's way of living.

A molecule with a longer circulation half-life would decrease the number of necessary administrations. Given the frequent injections associated with currently available FVIIa therapy and the potential for obtaining more optimal therapeutic FVIIa levels with concomitant enhanced therapeutic effect, there is a clear need for improved FVII or FVIIa-like molecules with a longer half-life in vivo.

Recombinant human coagulation factor VIIa (rFVIIa, NovoSeven; Novo Nordisk A/S, Copenhagen, Denmark) has proven to be efficacious for the treatment of bleeding episodes in hemophilia patients with inhibitors. A small fraction of patients may be refractory to rFVIIa treatment and could potentially benefit from genetically modified FVIIa molecules with increased potencies. To this end, FVIIa analogs with increased intrinsic activity have been investigated that exhibit superior hemostatic profiles in vitro (see e.g. WO02/077218 or WO05/074975, which are hereby incorporated by reference in their entirety, and Tranholm et al., 2003, Blood 102(10): 3615-20, which is also incorporated by reference). These analogs may also be used as more efficacious hemostatic agents in other indications where efficacy of rFVIIa has been observed, including in thrombocytopenia and trauma.

Thus, in some embodiments, the Factor VIIa analog that may be used in accordance with the invention is as described in WO02/077218 or WO05/074975. For example, the FVIIa analog may have a glutamine substituted for methionine at position 298 (i.e. M298Q-FVIIa). In certain exemplary embodiments, the FVIIa analog contains two additional mutations, valine at position 158 replaced by aspartic acid and glutamic acid at position 296 replaced by valine (i.e. V158D/E296V/M298Q-FVIIa). Additionally or alternatively, the Factor VIIa analog may have an alanine residue substitution for lysine at position 337 (i.e. V158D/E296V/M298Q/K337A-FVIIa). In still other embodiments, the Factor VIIa analog has a substitution or insertion selected from Q250C; P406C; and 407C, wherein a cysteine has also been introduced in the C-terminal sequence (see, e.g. U.S. Pat. No. 7,235,638, which is hereby incorporated by reference in its entirety). The Factor VIIa analog may further comprise a substitution or insertion at one or more of positions 247, 260, 393, 396, and/or 405.

In these or other embodiments, the Factor VIIa analog comprises a substitution relative to the sequence of native Factor VIIa selected from: (a) a substitution of Lys157 with an amino acid selected from the group consisting of Gly, Val, Ser, Thr, Asp, and Glu; (b) a substitution of Lys337 with an amino acid selected from the group consisting of Ala, Gly, Val, Ser, Thr, Gln, Asp, and Glu; (c) a substitution of Asp334 with any amino acid other than Ala or Asn; and (d) a substitution of Ser336 with any amino acid other than Ala or Cys (see e.g. U.S. Pat. No. 7,176,288, which is hereby incorporated by reference in its entirety). Additionally or alternatively, the Factor VIIa analog comprises a substitution of the Leu at position 305 of Factor VII with an amino acid residue selected from the group consisting of Val, Ile, Met, Phe, Trp, Pro, Gly, Ser, Thr, Cys, Tyr, Asn, Glu, Lys, Arg, His, Asp and Gln (see e.g. U.S. Pat. No. 6,905,683, which is hereby incorporated by reference in its entirety).

Thus, in one aspect, the present invention provides therapeutic agents comprising an elastic peptide, e.g., an elastin-like peptide (ELP) and a Factor VII/VIIa, or functional analog thereof. For example, in certain embodiments, the Factor VII/VIIa is human Factor VII/VIIa (e.g., SEQ ID NO: 33). The Factor VII/VIIa may be a functional analog of human Factor VII/VIIa, including functional fragments truncated at the N-terminus and/or C-terminus by from 1 to 10 amino acids, including by 1, 2, 3, or about 5 amino acids. Functional analogs may contain from 1 to 10 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the native sequence (e.g., SEQ ID NO: 33), and in each case retaining the activity of the peptide. For example, such analogs may have from 1 to about 5 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the native full length sequence, or with respect to one or both of the heavy and light chains. Such activity may be confirmed or assayed using any available assay, including those described herein. In these or other embodiments, the Factor VII/VIIa component has at least about 75%, 80%, 85%, 90%, 95%, or 98% identity with the native sequence (SEQ ID NO:33). The determination of sequence identity between two sequences (e.g., between a native sequence and a functional analog) can be accomplished using any alignment tool, including Tatusova et al., Blast 2 sequences—a new tool for comparing protein and nucleotide sequences, FEMS Microbiol Lett. 174:247-250 (1999).

In exemplary embodiments, the FactorVII-ELP fusion has the amino acid sequence of SEQ ID NO:58. SEQ ID NO:58 further comprises a TEV protease cleavage site between the FactorVII and ELP sequences, which may be beneficial for removing the ELP sequence post expression where desired. However, in accordance with the invention, the tev sequence may be entirely removed, or replaced with another linking sequence as disclosed herein.

In another aspect, the present invention provides methods for the treatment or prevention of bleeding-related disorders. The method comprises administering an effective amount of the therapeutic agent comprising an elastic peptide and a Factor VII/VIIa or functional analog thereof to a patient in need. In certain embodiments, the bleeding-related disorder is one or more of hemophilia (A or B), post-surgical bleeding, anticoagulation-induced bleeding, thrombocytopenia, Factor VII deficiency, Factor XI deficiency, bleeding in patients with liver disease, thrombasthenia, Bemard-Soulier syndrome, von Willebrand disease, and intracranial hemorrhage. Generally, the patient is a human or non-human animal (e.g., dog, cat, cow, or horse) patient. Preferably, the patient is human.

To characterize the in vitro binding properties of a suspected Factor VII/VIIa analog, or an elastic peptide-containing Factor VIIa analog, TF binding assays can be performed as described previously (See, e.g., Chaing et al., 1994, Blood 83(12): 3524-35). Briefly, recombinant human TF can be coated onto Immulon II plates in carbonate antigen buffer overnight at 4° C. BSA is also coated onto the plates for use as a control. Elastic peptide-containing Factor VIIa analogs may be added at various concentrations in TBS-T buffer. After several washes, monospecific polyclonal rabbit anti-human FVIIa sera is added and incubated for approximately an hour at room temperature. Next, goat anti-rabbit IgG conjugated to alkaline phosphatase is added, followed by the alkaline phosphatase substrate PNPP, which is used for detection. After subtraction of background, the absorbance at 405 nm is taken to be directly proportional to the degree of Factor VIIa binding to the immobilized TF. These values can then be compared to control plasma containing Factor VIIa.

The clotting ability of a Factor VII/VIIa analog or an elastic peptide-containing Factor VIIa analog can be measured in human FVII deficient plasma. In this assay, the elastic peptide-containing Factor VIIa analog diluted to varying concentrations directly into FVII deficient plasma. In a coagulometer, one part plasma±a FVIIa analog can be mixed with 2 parts Innovin™ (Dade, Miami, Fla.) prothrombin time reagent (recombinant human tissue factor with phospholipids and CaCl₂). Clot formation is detected optically and time to clotting measured. Clotting time (seconds) is compared to the mean clotting time of FVII-deficient plasma alone and plotted as the fractional clotting time versus FVIIa analog concentration.

Therapeutic Proteins

The present invention further provides therapeutic agents comprising an elastic peptide component and at least one therapeutic protein selected from Table 1. The elastic peptide (e.g., ELP) component and therapeutic protein may be coupled by recombinant fusion or chemical conjugation as described herein. Such therapeutic proteins are listed in Table 1 by protein name and GeneSeq Accession No. The amino acid sequence of each Therapeutic Protein, which is known in the art, is hereby incorporated by reference for each Therapeutic Protein listed in Table 1. Such therapeutic proteins are further described in U.S. patent or PCT publications that are also listed in Table 1, and such U.S. patent and PCT publications are hereby incorporated by reference, especially with respect to the structure of such therapeutic proteins and described functional analogs.

Table 1 further describes the biological activity of each listed Therapeutic Protein, as well as an exemplary assay for determining the activity of functional analogs or agents of the invention (e.g., fusion with an elastic peptide component). Generally, functional analogs of therapeutic proteins listed in Table 1 may include functional fragments truncated at the N-terminus and/or C-terminus by from 1 to 10 amino acids, including by 1, 2, 3, 4 or about 5 amino acids. Functional analogs may contain from 1 to 10 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the base sequence (e.g., as listed in Table 1), and in each case retaining the full or partial biological activity (as listed in Table 1) of the therapeutic protein. For example, functional analogs may have 1, 2, 3, 4, or 5 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the base sequence. Such activity may be confirmed or assayed using any available assay, including those described in the Table. In these or other embodiments, the therapeutic protein has at least about 75%, 80%, 85%, 90%, 95%, or 98% identity with the corresponding base sequence. The molecules may further comprise additional chemical modifications known for each in the art.

In some embodiments, the therapeutic protein (e.g., as selected from Table 1) has a size of less than about 25 kDa, or less than about 10 kDa, or less than about 5 kDa, and the corresponding therapeutic agent of the invention (e.g., comprising the ELP component) has a molecular weight of less than about 60 kDa, 55 kDa, 50 kDa, or 40 kDa.

Table 1 further lists preferred indications for each therapeutic protein, for which the corresponding therapeutic agent finds use, such as in a method for treatment or prevention related to such indication.

TABLE 1 PCT/Patent Reference Exemplary (the patents Identifier and (the sequences publications listed in this listed in this column are each column are Exemplary Activity Assay hereby each hereby (the publications listed in this column Therapeutic incorporated by incorporated are each hereby incorporated by Protein X reference) by reference) Biological Activity reference) Preferred Indication Y BMP-1 GeneSeq WO8800205 BMP1 belongs to the transforming growth BMP-1 activity can be determined using Induction of Cartilage, Acession P80618 factor-beta (TGFB) superfamily. Bone the following assays known in the art: Nat Tissue and Bone Growth, morphogenic proteins induce cartilage Genet. 2001 Jan; 27(1): 84-8; Eur J and Diabetes and bone formation, play important role Biochem 1996 Apr 1; 237(1): 295-302; J in nephrogesis, and play an important Biol Chem, Vol. 274, Issue 16, 10897-10902, role in the development of many organs, Apr. 16, 1999; and Hogan, B. L. M. including lung, heart, teeth, gut, skin, and (1996) Genes Dev. 10, 1580-1594. particularly the kidney. BMP-2 GeneSeq WO8800205 BMP-2 belongs to the transforming BMP-2 activity can be determined using the Induction of Cartilage, Accession P80619 growth factor-beta (TGFB) superfamily. following assays known in the art: Nat Tissue and Bone Growth, Bone morphogenic protein induces bone Genet. 2001 Jan; 27(1): 84-8; Eur J and Diabetes formation. Biochem 1996 Apr 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-2B GeneSeq U.S. Pat. No. 5,631,142 BMP-2b belongs to the transforming BMP-2b activity can be determined using Induction of Cartilage, Accession W24850 growth factor-beta (TGFB) superfamily. the following assays known in the art: Nat Tissue and Bone Growth, Bone morphogenic protein induces bone Genet. 2001 Jan; 27(1): 84-8; Eur J and Diabetes formation. Biochem 1996 Apr 1; 237(1): 295-302; I Biol Cbcre, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-4 GeneSeq WO0020591 BMP-4 belongs to the transforming BMP-4 activity can be determined using the Induction of Cartilage, Accession growth factor-beta (TGFB) superfamily. following assays known in the art: Nat Tissue and Bone Growth, B02796 Bone morphogenic protein induces bone Genet. 2001 Jan; 27(1): 84-8; Eur J and Diabetes formation. Biochem 1996 Apr 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-5 GeneSeq WO0020591 BMP-5 belongs to the transforming BMP-5 activity can be determined using the Induction of Cartilage, Accession growth factor-beta (TGFB) superfamily. following assays known in the art: Nat Tissue and Bone Growth, B02797 Bone morphogenic protein induces bone Genet. 2001 Jan; 27(1): 84-8; Eur J and Diabetes formation. Biochem 1996 Apr 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-6 GeneSeq U.S. Pat. No. 5,187,076 BMP-6 belongs to the transforming BMP-6 activity can be determined using the Induction of Cartilage, Accession growth factor-beta (TGFB) superfamily. following assays known in the art: Nat Tissue and Bone Growth, R32904 Bone morphogenic protein induces bone Genet. 2001 Jan; 27(1): 84-8; Eur J and Diabetes formation. Biochem 1996 Apr 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. Osteogenic GeneSeq WO973462 OP-1 belongs to the transforming growth OP-1 activity can be determined using the Induction of Cartilage, Protein-1; OP-1; Accession factor-beta (TGFB) superfamily. Bone following assays known in the art: Nat Tissue and Bone Growth, BMP-7 W34783 morphogenic protein induces bone Genet. 2001 Jan; 27(1): 84-8; Eur J and Diabetes formation. Biochem 1996 Apr 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. Osteogenic GeneSeq WO9406399 OP-2 belongs to the transforming growth OP-2 activity can be determined using the Induction of Cartilage, Protein-2 Accession R57973 factor-beta (TGFB) superfamily. Bone following assays known in the art: Nat Tissue and Bone Growth, morphogenic protein induces bone Genet. 2001 Jan; 27(1): 84-8; Eur J and Diabetes formation. Biochem 1996 Apr 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. GDP-1 GeneSeq WO9406449 Members of the TGF-beta family of The effect of GDF-1 on signaling can be Developmental disorders, Accession proteins initiate cell signaling by binding assayed by treating Primary BAECs Induction of Cartilage, R60961 to heteromeric receptor complexes of transferred with a construct called p3TP- Tissue and Bone Growth, type I (TbetaRI) and type II (TbetaRII) Lux, containing a TGF-beta responsive and Diabetes serine/threonine kinase receptors promoter fused to a reporter gene, and (reviewed by Massague, J. et al. (1994) measuring luciferase gene expression Trends Cell Biol. 4: 172 178; Miyazono, K. (Wrana et al., 1994, Nature 370: 341-347). et al. (1994) Adv. Immunol. 55: 181-220). Activation of this heteromeric receptor complex occurs when TGF-beta binds to TbetaRII, which then recruits and phosphorylates TbetaRI. Activated TbetaRI then propagates the signal to downstream targets (Chen, F. and Weinberg, R. A. (1995) PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341 347). BMP-9 GeneSeq WO9533830 BMP-9 belongs to the transforming BMP-9 activity can be determined using the Induction of Cartilage, Accession growth factor-beta (TGFB) superfamily. following assays known in the art: Nat Tissue and Bone Growth, R86903 Bone morphogenic protein induces bone Genet. 2001 Jan; 27(1): 84-8; Eur J and Diabetes formation. Biochem 1996 Apr 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-10 GeneSeq WO9426893 BMP-10 belongs to the transforming BMP-10 activity can be determined using Induction of Cartilage, Accession R66202 growth factor-beta (TGFB) superfamily. the following assays known in the art: Nat Tissue and Bone Growth, Bone morphogenic protein induces bone Genet. 2001 Jan; 27(1): 84-8; Eur J and Diabetes formation. Biochem 1996 Apr 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-12 GeneSeq WO9516035 BMP-12 belongs to the transforming BMP-12 activity can be determined using Induction of Cartilage, Accession R78734 growth factor-beta (TGFB) superfamily. the following assays known in the art: Nat Tissue and Bone Growth, Bone morphogenic protein induces bone Genet. 2001 Jan; 27(1): 84-8; Eur J and Diabetes formation. Biochem 1996 Apr 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-15 GeneSeq W09636710 BMP-15 belongs to the transforming BMP-15 activity can be determined using Induction of Cartilage, Accession W11261 growth factor-beta (TGFB) superfamily. the following assays known in the art: Nat Tissue and Bone Growth, Bone morphogenic protein induces bone Genet. 2001 Jan; 27(1): 84-8; Eur J and Diabetes formation. Biochem 1996 Apr 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-17 GeneSeq WO9929718 BMP-17 belongs to the transforming BMP-17 activity can be determined using Induction of Cartilage, Accession Y17870 growth factor-beta (TGFB) superfamily. the following assays known in the art: Nat Tissue and Bone Growth, Bone morphogenic protein induces bone Genet. 2001 Jan; 27(1): 84-8; Eur J and Diabetes formation. Biochem 1996 Apr 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-18 GeneSeq WO9929718 BMP-18 belongs to the transforming BMP-18 activity can be determined using Induction of Cartilage, Accession Y17871 growth factor-beta (TGFB) superfamily. the following assays known in the art: Nat Tissue and Bone Growth, Bone morphogenic protein induces bone Genet. 2001 Jan; 27(1): 84-8; Eur J and Diabetes formation. Biochem 1996 Apr 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. Inhibin alpha GeneSeq WO0020591 The inhibin beta A subunit joins the alpha Tumor suppressor activity of inhibin can be Tumor suppression. Accession B02806 subunit to form a pituitary FSH secretion determined using assays known in the art: inhibitor. Inhibin has been shown to Matzuk et al., Nature 1992 Nov. 26: 360 regulate gonadal stromal cell proliferation (6402); 313-9. negatively and to have tumour- suppressor activity. In addition, serum levels of inhibin have been shown to reflect the size of granulosa-cell tumors and can therefore be used as a marker for primary as well as recurrent disease. Inhibin beta GeneSeq WO0020591 The inhibin beta A subunit joins the alpha Tumor suppressor activity of inhibin can be Tumor suppression. Accession subunit to form a pituitary FSH secretion determined using assays known in the art: H02808 inhibitor. Inhibin has been shown to Matzuk et al., Nature 1992 Nov. 26: 360 regulate gonadal stromal cell proliferation (6402); 313-9. negatively and to have tumour- suppressor activity. In addition, serum levels of inhibin have been shown to reflect the size of granulosa-cell tumors and can therefore be used as a marker for primary as well as recurrent disease. Cerebus Protein GeneSeq WO9849296 Cerebus is believed to be involved in the BMP activity, in the presence of the BMP Antagonist useful for Accession inhibition of BMP activity antagonist Cerebus, can be determined Osteosarcoma, abnormal W86032 using the following assays known in the art: bone growth. Nat Genet. 2001 Jan; 27(1): 84-8; Eur J Biochem 1996 Apr 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. Soluble BMP GeneSeq WO9614579 Soluble BMP receptor kinase protein-3 is BMP activity, in the presence of the soluble BMP Antagonist useful for Receptor Kinase Accession involved in the binding of BMPs. Soluble antagonist BMP receptor kinase protein-3, Osteosarcoma, abnormal Protein-3 R95227 BMP receptor kinase protein-3 is useful can be determined using the following bone growth. as an antagonist for the inhibition of BMP assays known in the art: Nat Genet. 2001 activity. Jan; 27(1): 84-8; Eur J Biochem 1996 Apr 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP Processing GeneSeq WO9741250 BMPs belong to the transforming growth BMP activity, in the presence of the Furin, Bone formation or Enzyme Furin Accession factor-beta (TGFB) superfamily. Bone can be determined using the following Regeneration W36099 morphogenic protein induces bone assays known in the art: Nat Genet. 2001 Abnormalities formation. Jan; 27(1): 84-8; Eur J Biochem 1996 Apr 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. TGF-beta 1 GeneSeq WO9216228 Members of the TGF-beta family of The effect of TGF betas on signaling can Useful for treating cancer Accession proteins initiate cell signaling by binding be assayed by treating Primary BAECs and to promote wound R29657 to heteromeric receptor complexes of transfected with a construct called p3TP- healing. type I (TbetaRI) and type II (TbetaRII) Lux, containing a TGF-beta responsive serine/threonine kinase receptors promoter fused to a reporter gene, and (reviewed by Massague, J. et al. (1994) measuring luciferase gene expression Trends Cell Biol. 4: 172 178; Miyazono, K. (Wrana et al., 1994, Nature 370: 341-347). et al. (1994) Adv. Immunol. 55: 181-220). Activation of this heteromeric receptor complex occurs when TGF-beta. binds to TbetaRII, which then recruits and phosphorylates TbetaRI. Activated TbetaRI then propagates the signal to downstream targets (Chen, F. and Weinberg. R. A. (1995) PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341. TGF-beta 2 GeneSeq EP542679 Members of the TGF-beta family of The effect of TGF betas on signaling can Useful for treating cancer Accession proteins initiate cell signaling by binding be assayed by treating Primary BAECs and to promote wound R39659 to heteromeric receptor complexes of transfected with a construct called p3TP- healing. type I (TbetaRI) and type II (TbetaRII) Lux, containing a TGF-beta responsive serine/threonine kinase receptors promoter fused to a reporter gene, and (reviewed by Massague, J. et al. (1994) measuring luciferase gene expression Trends Cell Biol. 4: 172 178; Miyazono, K. (Wrana et al., 1994, Nature 370: 341-347). et al. (1994) Adv. Immunol. 55: 181-220). Activation of this heteromeric receptor complex occurs when TGF-beta. binds to TbetaRII, which then recruits and phosphorylates TbetaRI. Activated TbetaRI then propagates the signal to downstream targets (Chen, F. and Weinberg. R. A. (1995) PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341. ZTGF-beta 9 GeneSeq WO0015798 Members of the TGF-beta family of The effect of TGF betas on signaling can Useful for treating cancer Accession proteins initiate cell signaling by binding be assayed by treating Primary BAECs and to promote wound Y70654 to heteromeric receptor complexes of transfected with a construct called p3TP- healing. type I (TbetaRI) and type II (TbetaRII) Lux, containing a TGF-beta responsive serine/threonine kinase receptors promoter fused to a reporter gene, and (reviewed by Massague, J. et al. (1994) measuring luciferase gene expression Trends Cell Biol. 4: 172 178; Miyazono, K. (Wrana et al., 1994, Nature 370: 341-347). et al. (1994) Adv. Immunol. 55: 181-220). Activation of this heteromeric receptor complex occurs when TGF-beta. binds to TbetaRII, which then recruits and phosphorylates TbetaRI. Activated TbetaRI then propagates the signal to downstream targets (Chen, F. and Weinberg. R. A. (1995) PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341. Anti-TGF beta GB2305921 Members of the TGF-beta family of The effect of TGF betas on signaling in the Useful for control of family antibodies proteins initiate cell signaling by binding presence of an anti-TGF beta antibody, can fibrosis, immune, and to heteromeric receptor complexes of be assayed by treating Primary BAECs inflammatory disease. type I (TbetaRI) and type II (TbetaRII) transfected with a construct called p3TP- serine/threonine kinase receptors Lux, containing a TGF-beta responsive (reviewed by Massague, J. et al. (1994) promoter fused to a reporter gene, and Trends Cell Biol. 4: 172 178; Miyazono, K. measuring luciferase gene expression et al. (1994) Adv. Immunol. 55: 181-220). (Wrana et al., 1994, Nature 370: 341-347). Activation of this heteromeric receptor complex occurs when TGF-beta. binds to TbetaRII, which then recruits and phosphorylates TbetaRI. Activated TbetaRI then propagates the signal to downstream targets (Chen, F. and Weinberg. R. A. (1995) PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341. Latent TGF beta GeneSeq WO0012551 Members of the TGF-beta family of The effect of TGF betas on signaling in the Useful for inhibiting tissue binding protein II Accession proteins initiate cell signaling by binding presence of a TGF beta binding protein, or tumor growth. Y70552 to heteromeric receptor complexes of can be assayed by treating Primary BAECs type I (TbetaRI) and type II (TbetaRII) transfected with a construct called p3TP- serine/threonine kinase receptors Lux, containing a TGF-beta responsive (reviewed by Massague, J. et al. (1994) promoter fused to a reporter gene, and Trends Cell Biol. 4: 172 178; Miyazono, K. measuring luciferase gene expression et al. (1994) Adv. Immunol. 55: 181-220). (Wrana et al., 1994, Nature 370: 341-347). Activation of this heteromeric receptor complex occurs when TGF-beta. binds to TbetaRII, which then recruits and phosphorylates TbetaRI. Activated TbetaRI then propagates the signal to downstream targets (Chen, F. and Weinberg. R. A. (1995) PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341. MP52 GeneSeq WO9741250 Members of the TGF-beta family of The effect of TGF betas on signaling can Bone formation or Accession proteins initiate cell signaling by binding be assayed by treating Primary BAECs Regeneration W36100 to heteromeric receptor complexes of transfected with a construct called p3TP- Abnormalities type I (TbetaRI) and type II (TbetaRII) Lux, containing a TGF-beta responsive serine/threonine kinase receptors promoter fused to a reporter gene, and (reviewed by Massague, J. et al. (1994) measuring luciferase gene expression Trends Cell Biol. 4: 172 178; Miyazono, K. (Wrana et al., 1994, Nature 370: 341-347). et al. (1994) Adv. Immunol. 55: 181-220). Activation of this heteromeric receptor complex occurs when TGF-beta. binds to TbetaRII, which then recruits and phosphorylates TbetaRI. Activated TbetaRI then propagates the signal to downstream targets (Chen, F. and Weinberg. R. A. (1995) PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341. b57 Protein GeneSeq WO9837195 BMPs are involved in the induction of BMP activity, in the presence of b57 BMP Antagonist useful for Accession bone formation. Specific antagonists are protein, can be determined using the Osteosarcoma, abnormal W69293 useful is preventing this activity from following assays known in the art: Nat bone growth. occurring. Genet. 2001 Jan; 27(1): 84-8; Eur J Biochem 1996 Apr 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 1089-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Deve. 10, 1580-1594. Resistin GeneSeq WO0064920 This gcne belongs to the family defined by Ability of resistin to influence type II Type II diabetes and Accession mouse FIZZI and FIZZ3/Resistin genes. diabetes can be determined using assays Syndrome X. W69293 The characteristic feature of this family is known in the art: Pontoglio et al., J Clin the C-terminal stretch of 10 cys residues Invest 1998 May 15; 101(10): 2215-22. with identical spacing. The mouse homolog of this protein is secreted by adipocytes, may be the hormone potantially linking obesity to type II diabetes. Galectin-4 GeneSeq WO9703190 Galectins are a family of carbohydrate- Ability of Galectin-4 polypeptides to bind Lactose intolerance. Accession binding proteins characterized by an lactose can be determined using assays W11841 affinity for beta-galactoside containing known in the art: Wada, et al., J Biol Chem glycoconjugates. 1997 Feb 28; 272(9): 6078-86. APM-I; ACRP-30; GeneSeq W00026363 ACPR30 gene is exclusively expressed in Ability of ACRP30 polypeptides to Obesity, Metabolic Famoxin Accession adipose tissue. ACRP30 is thought to influence obesity and fat oxidation can be disorders, Lipid Y71035 increase fatty acid oxidation by muscle determined using assays known in the art: Metabolism; Hormone tissue. Fruebis et al., Proc Nat'l Acad Sci USA Secretion. 2001 Feb 13; 98(4): 2005-10. ACRP-30 GeneSeq WO0063376 ACPR30 gene is exclusively expressed in Ability of ACRP30 homologue Obesity, Metabolic Homologue; Accession adipose tissue. ACRP30 is thought to polypeptides to influence obesity and fat disorders, Lipid Complement B30234 increase fatty acid oxidation by muscle oxidation can be determined using assays Metabolism; Hormone Component Clq C tissue. known in the art: Fruebis et al., Proc Nat'l Secretion. Acad Sci USA 2001 Feb 13; 98(4): 2005-10. Calpain-10a GeneSeq WO0023603 Calpain is believed to play a role in insulin Ability of Calpain-10 to influence type II Diabetes mellitus; Accession secretion and insulin activity, and diabetes can be determined using assays Regulation of Insulin Y79567 therefore may be useful in the treatment known in the art: Pontoglio et al., J Clin secretory response; of type II diabetes. Invest 1998 May 15; 101(10): 2215-22. Insulin mediated glucose transport disorders. Calpain-10b GeneSeq WO0023603 Calpain is believed to play a role in insulin Ability of Calpain-10 to influence type II Diabetes mellitus; Accession secretion and insulin activity, and diabetes can be determined using assays Regulation of Insulin Y79568 therefore may be useful in the treatment known in the art: Pontoglio et al., J Clin secretory response; of type II diabetes. Invest 1998 May 15; 101(10): 2215-22. Insulin mediated glucose transport disorders. Calpain-10c GeneSeq WO0023603 Calpain is believed to play a role in insulin Ability of Calpain-10 to influence type II Diabetes mellitus; Accession secretion and insulin activity, and diabetes can be determined using assays Regulation of Insulin Y79569 therefore may be useful in the treatment known in the art: Pontoglio et al., J Clin secretory response; of type II diabetes. Invest 1998 May 15; 101(10): 2215-22. Insulin mediated glucose transport disorders. PDGF-D GeneSeq WO0027879 Vascular Endothelial Growth Factor. Proliferation assay using NR6R-3T3 cells Wound Healing; Accession (Rizzino 1988 Cancer Res. 48: 4266). Atherosclermis. Y71130 FasL GeneSeq WO9936079 Activities associated with apoptosis and Activity can be determined using Apoptosis-related Accession immune system functions. Apoptosis assays known in the art: disorders; Autoimmune Y28594 Walczak et al. (1996) EMBOJ 16: 5386-5397. disorders; Graft v-Host disorders. Chondro modulin- GeneSeq W00029579 Chondromodulin proteins are cartilage Ability of Chondromodulin-like protein to Antianglogenic agent; like protein Accession proteins thought to confer resistance to inhibit vascularization can be determined Osteoblast proliferation Y71262 anglogeneis, and thus are useful as anti- using assays known in the art: Hirakie et stimulator; prevents angiogenic agents that may have utility in al., J Biol Chem 1997 Dec 19; vascularization of cartilage combating cancer. 272(51): 32419-26. tissue; Useful to treat cancer. Patched GeneSeq U.S. Pat. No. 5,837,538 Patched is a tumour-suppressor receptor Ability of soluble Patched to bind to and Receptor for Hedgehog Accession for Sonic hedgehog (shh), which is a inhibit the activities of shh can be cellular proliferation W72969 protein that controls developmental determined using assays known in the art: signaling molecule. This patterning and growth. Stone et al., Nature 1996 Nov 14; receptor is useful as a 384(6605): 129-34. means of preventing cellular proliferation via the shh signaling pathway, thus useful for cancers. Patched-2 GeneSeq WO9953058 Patched is a tumour-suppressor receptor Ability of soluble Patched to bind to and Receptor for Hedgehog Accession for Sonic hedgehog (shh), which is a inhibit the activities of shh can be cellular proliferation Y43261 protein that controls developmental determined using assays known in the art: signaling molecule. This patterning and growth. Stone et al., Nature 1996 Nov 14; receptor is useful as a 384(6605): 129-34. means of preventing cellular proliferation via the shh signaling pathway, thus useful for cancers. Maspin; Protease GeneSeq WO9405804 Maspin is a member of the serpin family of The inhibitory effects cf Maspin and other Tumor suppressor which is Inhibitor 5 Accession serine protease inhibitors that is thought protease inhibitors can be assayed using down-regulated in breast R50938 to suppress tumor metastasis. methods known in the art such as a cancers. The maspin labeled protease substrate, for example, protein has tumour Universal Protease Substrate (casein, suppressing and invasion resorufin-labeled): Roche Molecular suppressing activity. Biochemicals, Cat. No. 1080733. Endostatin GeneSeq WO0064946 Endostatin is believed to inhibit effects of The inhibitory effects of endostatin can be Anti-angiogenic activity. Accession capillary endothelial cell proliferation. assayed using assays disclosed by Cao et Useful in the prevention B28399 al. (1996) J. Biol. Chem. 271 29461-29467. and/or treatment of cancers. aFGF; FGF-1 GeneSeq EP298723 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 cells Promotion of growth and Accession (Rizzino 1988 Cancer Res. 48: 4266); proliferation of cells, such P94037 Examples 23 and 39 disclosed herein. as epithelial cells and keratinocytes. Antagonists may be useful as anti- cancer agents. bFGF; FGF-2 GeneSeq FR2642086 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 cells Promotion of growth and Accession (Rizzino 1988 Cancer Res. 48: 4266); proliferation of cells, such R06685 Examples 23 and 39 disclosed herein. as epithelial cells and keratinocytes. Antagonists may be useful as anti- cancer agents. FGF-3; INT-2 GeneSeq WO9503831 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 cells Promotion of growth and Accession (Rizzino 1988 Cancer Res. 48: 4266); proliferation of cells, such R07824 Examples 23 and 39 disclosed herein. as epithelial cells and keratinocytes. Antagonists may be useful as anti- cancer agents. FGF-4; HST-1; GeneSeq WO9503831 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 cells Promotion of growth and HBGF-4 Accession (Rizzino 1988 Cancer Res. 48: 4266); proliferation of cells, such R07825 Examples 23 and 39 disclosed herein. as epithelial cells and keratinocytes. Antagonists may be useful as anti- cancer agents. FGF-5 GeneSeq WO9730155 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 cells Promotion of growth and Accession (Rizzino 1988 Cancer Res. 48: 4266); proliferation of cells, such W22600 Examples 23 and 39 disclosed herein. as epithelial cells and keratinocytes. Antagonists may be useful as anti- cancer agents. FGF-6; Heparin GeneSeq EP613946 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 cells Promotion of growth and binding secreted Accession (Rizzino 1988 Cancer Res. 48: 4266); proliferation of cells, such transforming R58555 Examples 23 and 39 disclosed herein. as epithelial cells and factor-2 keratinocytes. Antagonists may be useful as anti- cancer agents. FGF-8 GeneSeq WO9524928 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 cells Promotion of growth and Accession (Rizzino 1988 Cancer Res. 48: 4266); proliferation of cells, such R80783 Examples 23 and 39 disclosed herein. as epithelial cells and keratinocytes. Antagonists may be useful as anti- cancer agents. FGF-9; Gila GeneSeq WO9503831 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 cells Promotion of growth and activating factor Accession (Rizzino 1988 Cancer Res. 48: 4266); proliferation of cells, such R70822 Examples 23 and 39 disclosed herein. as epithelial cells and keratinocytes. Antagonists may be useful as anti- cancer agents. FGF-12; GeneSeq WO9635708 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 cells Promotion of growth and Fibroblast growth Accession (Rizzino 1988 Cancer Res. 48: 4266); proliferation of cells, such factor homologous W06309 Examples 23 and 39 disclosed herein. as epithelial cells and factor-1 keratinocytes. Antagonists may be useful as anti- cancer agents. FGF-15 GeneSeq WO9927100 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 cells Promotion of growth and Accession (Rizzino 1988 Cancer Res. 48: 4266); proliferation of cells, such Y08582 Examples 23 and 39 disclosed herein. as epithelial cells and keratinocytes. Antagonists may be useful as anti- cancer agents. FGF-16 GeneSeq WO9918128 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 cells Promotion of growth and Accession (Rizzino 1988 Cancer Res. 48: 4266); proliferation of cells, such Y05474 Examples 23 and 39 disclosed herein. as epithelial cells and keratinocytes. Antagonists may be useful as anti- cancer agents. FGF-18 GeneSeq WO9927100 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 cells Promotion of growth and Accession (Rizzino 1988 Cancer Res. 48: 4266); proliferation of cells, such Y08590 Examples 23 and 39 disclosed herein. as epithelial cells and keratinocytes. Antagonists may be useful as anti- cancer agents. fit-3 ligand GeneSeq EP627487 Stem Cell Progenitor Chemokine activities can be determined Promotion of immune cell Accession using assays known in the art: Methods in growth and/or R67541 Molecular Biology, 2000, vol. 138: differentiation. Chemokine Protocols. Edited by: A. E. I. Proudfoot, T. N. C. Wells, and C. A. Power. © Humana Press Inc., Totowa, NJ. VEGF-110 GeneSeq WO0013702 Promotes the growth and/or proliferation VEGF activity can be determined using Promotion of growth and Accession of endothelial cells. assays known in the art, such as those proliferation of cells, such Y69417 disclosed in International Publication No. as vascular endothelial WO0045835, for example. cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGB-121 GeneSeq WO0071713 Promotes the growth and/or proliferation VEGF activity can be determined using Promotion of growth and Accession of endothelial cells. assays known in the art, such as those proliferation of cells, such B50432 disclosed in International Publication No. as vascular endothelial WO0045835, for example. cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-138 GeneSeq WO9940197 Promotes the growth and/or proliferation VEGF activity can be determined using Promotion of growth and Accession of endothelial cells. assays known in the art, such as those proliferation of cells, such Y43483 disclosed in International Publication No. as vascular endothelial WO0045835, for example. cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-145 GeneSeq WO0013702 Promotes the growth and/or proliferation VEGF activity can be determined using Promotion of growth and Accession of endothelial cells. assays known in the art, such as those proliferation of cells, such Y69413 disclosed in International Publication No. as vascular endothelial WO0045835, for example. cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-162 GeneSeq W09940197 Promotes the growth and/or proliferation VEGF activity can be determined using Promotion of growth and Accession of endothelial cells. assays known in the art, such as those proliferation of cells, such Y43484 disclosed in International Publication No. as vascular endothelial WO0045835, for example. cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-165 GeneSeq WO0013702 Promotes the growth and/or proliferation VEGF activity can be determined using Promotion of growth and Accession of endothelial cells. assays known in the art, such as those proliferation of cells, such Y69414 disclosed in International Publication No. as vascular endothelial WO0045835, for example. cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-182 GeneSeq W09940197 Promotes the growth and/or proliferation VEGF activity can be determined using Promotion of growth and Accession of endothelial cells. assays known in the art, such as those proliferation of cells, such Y43483 disclosed in International Publication No. as vascular endothelial WO0045835, for example. cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-189 GeneSeq WO0013702 Promotes the growth and/or proliferation VEGF activity can be determined using Promotion of growth and Accession of endothelial cells. assays known in the art, such as those proliferation of cells, such Y69415 disclosed in International Publication No. as vascular endothelial WO0045835, for example. cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-206 GeneSeq W00013702 Promotes the growth and/or proliferation VEGF activity can be determined using Promotion of growth and Accession of endothelial cells. assays known in the art, such as those proliferation of cells, such Y69416 disclosed in International Publication No. as vascular endothelial WO0045835, for example. cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-D GeneSeq WO9807832 Promotes the growth and/or proliferation VEGF activity can be determined using Promotion of growth and Accession of endothelial cells. assays known in the art, such as those proliferation of cells, such W53240 disclosed in International Publication No. as vascular endothelial WO0045835, for example. cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-E; VEGF-X GeneSeq W09947677 Promotes the growth and/or proliferation VEGF activity can be determined using Promotion of growth and Accession of endothelial cells. assays known in the art, such as those proliferation of cells, such Y33679 disclosed in International Publication No. as vascular endothelial WO0045835, for example. cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF Receptor; GeneSeq WO9831794 Receptor for VEGF polypeptides VEGF activity, in the presence of flk-1 VEGF Receptor. Fusion KDR; flk-1 Accession polypeptides, can be determined using protein with the W69679 assays known in the art, such as those extracellular domain is disclosed in International Publication No. useful as an anti- WO0045835, for example. angiogenic agent. Antagonists may be useful in the promotion of angiogenesis. Soluble VEGF GeneSeq U.S. Pat. No. 5,712,380 Receptor for VEGF polypeptides VEGF activity, in the presence of VEGF VEGF Receptor. Fusion Receptor Accession Receptor polypeptides, can be determined protein with the W47037 using assays known in the art, such as extracellular domain is those disclosed in International useful as an anti- Publication No. WO0045835, for example. angiogenic agent. Antagonists may be useful in the promotion of angiogenesis. flt-1 GeneSeq WO0021560 Receptor for VEGF polypeptides VEGF activity, in the presence of flt-1 VEGF Receptor. Fusion Accession polypeptides, can be determined using protein with the Y70751 assays known in the art, such as those extracellular domain is disclosed in International Publication No. useful as an anti- WO0045835, for example. angiogenic agent. Antagonists may be useful in the promotion of angiogenesis. VEGF R-3; flt-4 GeneSeq WO0058511 Receptor for VEGF polypeptides VEGF activity, in the presence of flt-4 VEGF Receptor. Fusion Accession polypeptides, can be determined using protein with the B29047 assays known in the art, such as those extracellular domain is disclosed in International Publication No. useful as an anti- WO0045835, for example. angiogenic agent. Antagonists may be useful in the promotion of angiogenesis. Neuropilin-1 GeneSeq WO9929858 Vascular Endothelial Growth Factor VEGF activity can be determined using Promotion of growth and Accession assays known in the art, such as those proliferation of cells, such Y06319 disclosed in International Publication No. as vascular endothelial WO0045835, for example. cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Neuropilin-2 GeneSeq WO9929858 Vascular Endothelial Growth Factor VEGF activity can be determined using Promotion of growth and Accession assays known in the art, such as those proliferation of cells, such Y03618 disclosed in International Publication No. as vascular endothelial WO0045835, for example. cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Human fast twitch GeneSeq W09730085 Troponins are contractile proteins that are Ability of soluble Troponins to inhibit Anti-angiogenesis skeletal muscle Accession thought to inhibit angiogencsis. High anglogenesis can be determined using troponin C W22597 levels may contribute to the difficulty assays known in the art:. Proc Natl Acad encountered in revascularizing the Sci USA 1999 Mar 16; 96(6): 2645-50. ischemic myocardium after cardiovascular injury. Human fast twitch GeneSeq W09730085 Troponins are contractile proteins that are Ability of soluble Troponins to inhibit Anti-angiogenesis skeletal muscle Accession thought to inhibit angiogencsis. High anglogenesis can be determined using troponin I W18054 levels may contribute to the difficulty assays known in the art:. Proc Natl Acad encountered in revascularizing the Sci USA 1999 Mar 16; 96(6): 2645-50. ischemic myocardium after cardiovascular injury. Human fast twitch GeneSeq W09730085 Troponins are contractile proteins that are Ability of soluble Troponins to inhibit Anti-angiogenesis skeletal muscle Accession thought to inhibit angiogencsis. High anglogenesis can be determined using troponin T W22599 levels may contribute to the difficulty assays known in the art:. Proc Natl Acad encountered in revascularizing the Sci USA 1999 Mar 16; 96(6): 2645-50. ischemic myocardium after cardiovascular injury. fragment. GeneSeq W09719955 Troponins are contractile proteins that are Ability of soluble Troponins to inhibit Anti-angiogenesis myofibrillar protein Accession thought to inhibit angiogencsis. High anglogenesis can be determined using troponin I W18053 levels may contribute to the difficulty assays known in the art:. Proc Natl Acad encountered in revascularizing the Sci USA 1999 Mar 16; 96(6): 2645-50. ischemic myocardium after cardiovascular injury. myofibrillar protein GeneSeq W09719955 Troponins are contractile proteins that are Ability of soluble Troponins to inhibit Anti-angiogenesis troponin I Accession thought to inhibit angiogencsis. High anglogenesis can be determined using W18054 levels may contribute to the difficulty assays known in the art:. Proc Natl Acad encountered in revascularizing the Sci USA 1999 Mar 16; 96(6): 2645-50. ischemic myocardium after cardiovascular injury. Troponin peptides GeneSeq WO9933874 Troponins are contractile proteins that are Ability of soluble Troponins to inhibit Anti-angiogenesis Accessions thought to inhibit angiogencsis. High anglogenesis can be determined using Y29581, Y29582, levels may contribute to the difficulty assays known in the art:. Proc Natl Acad Y29583, Y29584, encountered in revascularizing the Sci USA 1999 Mar 16; 96(6): 2645-50. Y29585, and ischemic myocardium after cardiovascular Y29586 injury. Human fast twitch GeneSeq WO0054770 Troponins are contractile proteins that are Ability of soluble Troponins to inhibit Anti-angiogenesis skeletal muscle Accession thought to inhibit angiogencsis. High anglogenesis can be determined using Troponin subunit C B00134 levels may contribute to the difficulty assays known in the art:. Proc Natl Acad encountered in revascularizing the Sci USA 1999 Mar 16; 96(6): 2645-50. ischemic myocardium after cardiovascular injury. Human fast twitch GeneSeq WO0054770 Troponins are contractile proteins that are Ability of soluble Troponins to inhibit Anti-angiogenesis skeletal muscle Accession thought to inhibit angiogencsis. High anglogenesis can be determined using Troponin subunit I B00135 levels may contribute to the difficulty assays known in the art:. Proc Natl Acad Protein encountered in revascularizing the Sci USA 1999 Mar 16; 96(6): 2645-50. ischemic myocardium after cardiovascular injury. Human fast twitch GeneSeq WO0054770 Troponins are contractile proteins that are Ability of soluble Troponins to inhibit Anti-angiogenesis skeletal muscle Accession thought to inhibit angiogencsis. High anglogenesis can be determined using Troponin subunit T B00136 levels may contribute to the difficulty assays known in the art:. Proc Natl Acad encountered in revascularizing the Sci USA 1999 Mar 16; 96(6): 2645-50. ischemic myocardium after cardiovascular injury. Activator Inbibitor- GeneSeq WO9013648 PAIs are believed to play a role in cancer, Methods that measure plasminogen Anti-angiogenesis; blood- 1; PAI-1 Accession and cardiovascular disease and blood- activator inhibitor (PAI) activity are known clotting disorders. R08411 clotting disorders. in the art, for example, assay the ability of PAI to inhibit tissue plasminogen activator (tPA) or urokinase (uPA): J Biochem Biophys Methods 2000 Sep 11; 45(2): 127-40, Breast Cancer Res Treat 1996; 41(2): 141-6. Methods that measure anti-angiogenesis activity are known in the art, for example, Proc Natl Acad Sci USA 1999 Mar 16; 96(6): 2645-50. Plasminogen GeneSeq DE3722673 PAIs are believed to play a role in cancer, Methods that measure plasminogen Anti-angiogenesis; blood- Activator Inhibitor- Accession and cardiovascular disease and blood- activator inhibitor (PAI) activity are known clotting disorders. 2; PAI-2 P94160 clotting disorders. in the art, for example, assay the ability of PAI to inhibit tissue plasminogen activator (tPA) or urokinase (uPA): J Biochem Biophys Methods 2000 Sep 11; 45(2): 127-40, Breast Cancer Res Treat 1996; 41(2): 141-6. Methods that measure anti-angiogenesis activity are known in the art, for example, Proc Natl Acad Sci USA 1999 Mar 16; 96(6): 2645-50. Activator Inhibitor- GeneSeq WO9102057 PAIs are believed to play a role in cancer, Methods that measure plasminogen Anti-angiogenesis; blood- 2; PAI-2 Accession and cardiovascular disease and blood- activator inhibitor (PAI) activity are known clotting disorders. R10921 clotting disorders. in the art, for example, assay the ability of PAI to inhibit tissue plasminogen activator (tPA) or urokinase (uPA): J Biochem Biophys Methods 2000 Sep 11; 45(2): 127-40, Breast Cancer Res Treat 1996; 41(2): 141-6. Methods that measure anti-angiogenesis activity are known in the art, for example, Proc Natl Acad Sci USA 1999 Mar 16; 96(6): 2645-50. Human PAI-1 GeneSeq WO9105048 PAIs are believed to play a role in cancer, Methods that measure plasminogen Anti-angiogenesis; blood- mutants Accessions and cardiovascular disease and blood- activator inhibitor (PAI) activity are known clotting disorders. R11755, R11756, clotting disorders. in the art, for example, assay the ability of R11757, R11758, PAI to inhibit tissue plasminogen activator R11759, R11760, (tPA) or urokinase (uPA): J Biochem R11761, R11762 Biophys Methods 2000 Sep 11; 45(2): 127-40, and R11763 Breast Cancer Res Treat 1996; 41(2): 141-6. Methods that measure anti-angiogenesis activity are known in the art, for example, Proc Natl Acad Sci USA 1999 Mar 16; 96(6): 2645-50. CXCR3; CXC GeneSeq WO0018431 Chemokines are a family of related small, Chemokine activities can be determined Soluble CXCR3 Accession secreted proteins involved in biological using assays known in the art: Methods in polypeptides may be useful Y79372 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: for inhibiting chemokine angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, activities and viral infection. Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ. including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Modified Rantes GeneSeq WO9737005 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders. Accession secreted proteins involved in biological using assays known in the art: Methods in W38129 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ. including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. RANTES GeneSeq EP905240 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders. Accession secreted proteins involved in biological using assays known in the art: Methods in Y05299 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ. including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. MCI-Ia GeneSeq WO9509232 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders. Accession secreted proteins involved in biological using assays known in the art: Methods in R73914 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ. including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. MCP-Ib GeneSeq WO9929728 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders. Accession secreted proteins involved in biological using assays known in the art: Methods in Y26176 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ. including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. MCP-I receptor GeneSeq WO9519436 Chemokines are a family of related small, Chemokine activities can be determined Soluble MCP-1 Receptor Accession secreted proteins involved in biological using assays known in the art: Methods in polypeptides may be useful R79165 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: for inhibiting chemokine angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, activities and viral infection. Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ. including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. MCP-3 GeneSeq W09509232 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders. Accession secreted proteins involved in biological using assays known in the art: Methods in R73915 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ. including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. MCP-4 receptor GeneSeq W09809171 Chemokines are a family of related small, Chemokine activities can be determined Soluble MCP-4 Receptor Accession secreted proteins involved in biological using assays known in the art: Methods in polypeptides may be useful W56689 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: for inhibiting chemokine angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, activities and viral infection. Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ. including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. RANTES receptor GeneSeq U.S. Pat. No. 5,652,133 Chemokines are a family of related small, Chemokine activities can be determined Soluble RANTES Receptor Accession secreted proteins involved in biological using assays known in the art: Methods in polypeptides may be useful W29588 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: for inhibiting chemokine angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, activities and viral infection. Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ. including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. CCR5 variant GeneSeq WO9854317 Chemokines are a family of related small, Chemokine activities can be determined Soluble CCR5 polypeptides Accession secreted proteins involved in biological using assays known in the art: Methods in may be useful for inhibiting W88238 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: chemokine activities and angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, viral infection. Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ. including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. CCR7 GeneSeq U.S. Pat. No. 6,153,441 Chemokines are a family of related small, Chemokine activities can be determined Soluble CCR7 polypeptides Accession secreted proteins involved in biological using assays known in the art: Methods in may be useful for inhibiting B50859 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: chemokine activities and angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, viral infection. Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ. including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. CXC3 GeneSeq WO9727299 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders. Accession secreted proteins involved in biological using assays known in the art: Methods in W23345 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ. including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Eotaxin GeneSeq WO9700960 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders. Accession secreted proteins involved in biological using assays known in the art: Methods in W10099 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ. including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Neurotactin GeneSeq U.S. Pat. No. 6,013,257 Neurotactin may play a role in Chemotactic leukocyte migration assays Immune disorders. Accessions WO9742224 chemotactic leukocyte migration and brain are known in the art, for example: J. Y77537, W34307, inflammation processes. Immunol. Methods 33, ((1980)); Nature Y53259, and, 1997 Jun 5; 387(6633): 611-7. Y77539 Human CKbeta-9 GeneSeq U.S. Pat. No. 6,153,441 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders. Accession secreted proteins involved in biological using assays known in the art: Methods in B50860 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ. including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Lymphotactin GeneSeq WO0073320 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders. Accession secreted proteins involved in biological using assays known in the art: Methods in B50052 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ. including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G. MIP-3 alpha GeneSeq WO9801557 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders. Accession secreted proteins involved in biological using assays known in the art: Methods in W44398 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ. including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G. MIP-3 beta GeneSeq WO9801557 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders. Accession secreted proteins involved in biological using assays known in the art: Methods in W44399 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ. including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G. MIP-Gamma GeneSeq WO9504158 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders. Accession secreted proteins involved in biological using assays known in the art: Methods in R70798 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ. including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G. Stem Cell GeneSeq WO9104274 Chemokines are a family of related small, Chemokine activities can be determined Hematopoietic growth Inhibitory Accession secreted proteins involved in biological using assays known in the art: Methods in factors. Factor R11553 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ. including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G. thrombopoietin GeneSeq WO9521920 Thrombopoietin is involved in the Thrombopoietin (TPO) can be assayed to Hematopoietic growth Accession regulation of the growth and differentiation determine regulation of growth and factors. R79905 of megakaryocytes and preceptors differentiation of megakaryocytes. Mol thereof. Cell Biol 2001 Apr; 21(8): 2659-70; Exp Hematol 2001 Jan; 29(1): 51-8 and within. c-kit ligand; GeneSeq EP992579 and C-kit ligan is thought to stimulate the Chemokine activities can be determined Hematopoietic growth SCF; Mast cell Accession EP676470 proliferation of mast cells, and is able to using assays known in the art: Methods in factors. growth factor; Y53284, R83978 augment the proliferation of both myeloid Molecular Biology, 2000, vol. 138: MGF; and R83977 and lymphoid hematopoietic progenitors in Chemokine Protocols. Edited by: A. E. I. Proudfoot, Fibrosarcoma- bone marrow culture. C-kit ligand is also T. N. C. Wells, and C. A. Power. derived stem though to act synergistically with other © Humana Press Inc., Totowa, NJ. cell factor cytokines. Platelet derived GeneSeq WO0066736 Vascular Endothelial Growth Factor VEGF activity can be determined using Promotion of growth and growth factor Accession B48653 assays known in the art, such as those proliferation of cells, such disclosed in International Publication No. as vascular endothelial WO0045835, for example. cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Melanoma GeneSeq WO9503328 Melanoma inhibiting protein has Tumor suppressor activity of melanoma Cancer; melanoma inhibiting protein Accession R69811 melanoma-inhibiting activity and can be inhibiting protein can be determined using used to treat cancer (melanoma, assays known in the art: Matzuk et al., glioblastoma, neuroblastoma, small cell Nature 1992 Nov 26; 360(6402): 313-9. lung cancer, neuroectodermal tumors) or as an immunosuppressant (it inhibits IL-2 or phytohaemagglutinin induced proliferation of peripheral blood lymphocytes. Glioma-derived GeneSeq EP399816 Vascular Endothelial Growth Factor VEGF activity can be determined using Promotion of growth and growth factor Accession R08120 assays known in the art, such as those proliferation of cells, such disclosed in International Publication No. as vascular endothelial WO0045835, for example. cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Platelet derived GeneSeq EP682110 Vascular Endothelial Growth Factor VEGF activity can be determined using Promotion of growth and growth factor Accession R84759 assays known in the art, such as those proliferation of cells, such precursor A disclosed in International Publication No. as vascular endothelial WO0045835, for example. cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Platelet derived GeneSeq EP682110 Vascular Endothelial Growth Factor VEGF activity can be determined using Promotion of growth and growth factor Accession R84760 assays known in the art, such as those proliferation of cells, such precursor B disclosed in International Publication No. as vascular endothelial WO0045835, for example. cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Platelet derived GeneSeq EP282317 Vascular Endothelial Growth Factor VEGF activity can be determined using Promotion of growth and growth factor Bvsis Accession P80595 assays known in the art, such as those proliferation of cells, such and P80596 disclosed in International Publication No. as vascular endothelial WO0045835, for example. cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Placental Growth GeneSeq WO9206194 Vascular Endothelial Growth Factor VEGF activity can be determined using Promotion of growth and Factor Accessions assays known in the art, such as those proliferation of cells, such R23059 and disclosed in International Publication No. as vascular endothelial R23060 WO0045835, for example. cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Placental Growth GeneSeq DE19748734 Vascular Endothelial Growth Factor VEGF activity can be determined using Promotion of growth and Factor-2 Accession Y08289 assays known in the art, such as those proliferation of cells, such disclosed in International Publication No. as vascular endothelial WO0045835, for example. cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Thrombopoietin GeneSeq WO0000612 Thrombopoietin is involved in the Thrombopoietin (TPO) can be assayed to Thrombocytopenia, cancer. derivative1 Accession Y77244 regulation of the growth and differentiation determine regulation of growth and of megakaryocytes and preceptors differentiation of megakaryocytes. Mol thereof. Cell Biol 2001 Apr; 21(8): 2659-70; Exp Hematol 2001 Jan; 29(1): 51-8 and within. Thrombopoietin GeneSeq WO0000612 Thrombopoietin is involved in the Thrombopoietin (TPO) can be assayed to Thrombocytopenia, cancer. derivative2 Accession Y77255 regulation of the growth and differentiation determine regulation of growth and of megakaryocytes and preceptors differentiation of megakaryocytes. Mol thereof. Cell Biol 2001 Apr; 21(8): 2659-70; Exp Hematol 2001 Jan; 29(1): 51-8 and within. Thrombopoietin GeneSeq WO0000612 Thrombopoietin is involved in the Thrombopoietin (TPO) can be assayed to Thrombocytopenia, cancer. derivative3 Accession Y77262 regulation of the growth and differentiation determine regulation of growth and of megakaryocytes and preceptors differentiation of megakaryocytes. Mol thereof. Cell Biol 2001 Apr; 21(8): 2659-70; Exp Hematol 2001 Jan; 29(1): 51-8 and within. Thrombopoietin GeneSeq WO0000612 Thrombopoietin is involved in the Thrombopoietin (TPO) can be assayed to Thrombocytopenia, cancer. derivative4 Accession Y77267 regulation of the growth and differentiation determine regulation of growth and of megakaryocytes and preceptors differentiation of megakaryocytes. Mol thereof. Cell Biol 2001 Apr; 21(8): 2659-70; Exp Hematol 2001 Jan; 29(1): 51-8 and within. Thrombopoietin GeneSeq WO0000612 Thrombopoietin is involved in the Thrombopoietin (TPO) can be assayed to Thrombocytopenia, cancer. derivative5 Accession Y77246 regulation of the growth and differentiation determine regulation of growth and of megakaryocytes and preceptors differentiation of megakaryocytes. Mol thereof. Cell Biol 2001 Apr; 21(8): 2659-70; Exp Hematol 2001 Jan; 29(1): 51-8 and within. Thrombopoietin GeneSeq WO0000612 Thrombopoietin is involved in the Thrombopoietin (TPO) can be assayed to Thrombocytopenia, cancer. derivative6 Accession Y77253 regulation of the growth and differentiation determine regulation of growth and of megakaryocytes and preceptors differentiation of megakaryocytes. Mol thereof. Cell Biol 2001 Apr; 21(8): 2659-70; Exp Hematol 2001 Jan; 29(1): 51-8 and within. Thrombopoietin GeneSeq WO0000612 Thrombopoietin is involved in the Thrombopoietin (TPO) can be assayed to Thrombocytopenia, cancer. derivative7 Accession Y77256 regulation of the growth and differentiation determine regulation of growth and of megakaryocytes and preceptors differentiation of megakaryocytes. Mol thereof. Cell Biol 2001 Apr; 21(8): 2659-70; Exp Hematol 2001 Jan; 29(1): 51-8 and within. Fractalkine GeneSeq U.S. Pat. No. 6,043,086 Fractalkine is believed to play a role in Fractalkine activity can be determined Immune disorders. Accession Y53255 chemotactic leukocyte migration and using Chemotactic leukocyte migration neurological disorders. assays known in the art, for example: J. Immunol. Methods 33, ((1980)); Nature 1997 Jun 5; 387(6633): 611-7. CXC3 GeneSeq WO9757599 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders. Accession secreted proteins involved in biological using assays known in the art: Methods in W23345 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ. including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. CCR7 GeneSeq U.S. Pat. No. 6,153,441 Chemokines are a family of related small, Chemokine activities can be determined Soluble CCR7 polypeptides Accession B50859 secreted proteins involved in biological using assays known in the art: Methods in may be useful for inhibiting processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: chemokine activities and angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, viral infection. Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ. including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Nerve Growth GeneSeq EP414151 Nerve Growth Factor Proliferation assay using NR6R-3T3 cells Neurological disorders, Factor-beta Accession R11474 (Rizzino 1988 Cancer Res. 48: 4266) cancer Nerve Growth GeneSeq EP859056 Nerve Growth Factor Proliferation assay using NR6R 3T3 cells Neurological disorders, Factor-beta2 Accession (Rizzino 1988 Cancer Res. 48: 4266 cancer W69725 Neurotrophin-3 GeneSeq WO9821234 Neurotrophins regulate neuronal cell Trk tyrosine kinase activation assays Neurological disorders, Accession survival and synaptic plasticity. known in the art can be used to assay for cancer W8889 neurotrophin activity, for example, Proc Natl Acad Sci USA 2001 Mar 13; 98(6): 3555-3560. Neurotrophin-3 GeneSeq WO9325684 Neurotrophins regulate neuronal cell Trk tyrosine kinase activation assays Neurological disorders, Accession R47100 survival and synaptic plasticity. known in the art can be used to assay for cancer neurotrophin activity, for example, Proc Natl Acad Sci USA 2001 Mar 13; 98(6): 3555-3560. Neurotrophin-4a GeneSeq WO9325684 Neurotrophins regulate neuronal cell Trk tyrosine kinase activation assays Neurological disorders, Accession R47101 survival and synaptic plasticity. known in the art can be used to assay for cancer neurotrophin activity, for example, Proc Natl Acad Sci USA 2001 Mar 13; 98(6): 3555-3560. 13; 98(6): 3555-3560 Neurotrophin-4b GeneSeq WO9325684 Neurotrophins regulate neuronal cell Trk tyrosine kinase activation assays Neurological disorders, Accession R47102 survival and synaptic plasticity. known in the art can be used to assay for cancer tyrosine kinases. neurotrophin activity, for example, Proc Natl Acad Sci USA 2001 Mar 13; 98(6): 3555-3560. Neurotrophin-4c GeneSeq WO9325684 Neurotrophins regulate neuronal cell Trk tyrosine kinase activation assays Neurological disorders, Accession R47103 survival and synaptic plasticity. known in the art can be used to assay for cancer tyrosine kinases. neurotrophin activity, for example, Proc Natl Acad Sci USA 2001 Mar 13; 98(6): 3555-3560. Neurotrophin-4d GeneSeq WO9325684 Neurotrophins regulate neuronal cell Trk tyrosine kinase activation assays Neurological disorders, Accession R47102 survival and synaptic plasticity. known in the art can be used to assay for cancer tyrosine kinases. neurotrophin activity, for example, Proc Natl Acad Sci USA 2001 Mar 13; 98(6): 3555-3560. Platelet-Derived GeneSeq U.S. Pat. No. 5,219,739 Vascular Endothelial Growth Factor VEGF activity can be determined using Promotion of growth and Growth Factor Accession R38918 assays known in the art, such as those proliferation of cells, such A chain disclosed in International Publication No. as vascular endothelial W00045835, for example. cells. Hematopoietic and immune disorders. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer Platelet-Derived GeneSeq U.S. Pat. No. 5,219,739 Vascular Endothelial Growth Factor VEGF activity can be determined using Promotion of growth and Growth Factor Accession R38919 assays known in the art, such as those proliferation of cells, such B chain disclosed in International Publication No. as vascular endothelial W00045835, for example. cells. Hematopoietic and immune disorders. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer Stromal Derived GeneSeq WO9948528 Stromal Growth Factor Proliferation assay using NR6R-3T3 cells Hematopoietic, immune Factor-1 alpha Accession (Rizzino 1988 Cancer Res. 48: 4266) disorders, cancer Y39995 Stromal Derived GeneSeq CA2117953 Stromal Growth Factor Proliferation assay using NR6R-3T3 cells Hematopoietic, immune Factor-1 beta Accession (Rizzino 1988 Cancer Res. 48: 4266) disorders, cancer R75420 Tarc GeneSeq WO9711969 Chemotactic for T lymphocytes. May play Chemotactic leukocyte migration assays Antiinflammatory. Immune Accession a role in T-cell development. Thought to are known in the art, for example: J. disorders, cancer W14917 bind CCR8 and CCR4 Immunol. Methods 33 ((1980)) Prolactin GeneSeq WO9521625 Prolactin is involved in immune cell Immune coil proliferation and suppression Reproductive system Accession R78691 proliferation and apoptosis. of apoptosis by prolactin can be assayed disorders, cancer. by methods well-known in the art, for example, Buckley, AR and Buckley DJ, Ann N Y Acad Sci 2000; 917: 522-33, and within. Prolactin2 GeneSeq U.S. Pat. No. 5,955,346 Prolactin is involved in immune cell Immune coil proliferation and suppression Reproductive system Accession proliferation and apoptosis. of apoptosis by prolactin can be assayed disorders, cancer. Y31764 by methods well-known in the art, for example, Buckley, AR and Buckley DJ, Ann N Y Acad Sci 2000; 917: 522-33, and within. Follicle stimulating GeneSeq EP974359 FSH stimulates secretion of interleukin-1 FSH activities can be determined using Reproductive system hormone Alpha Accession by cells isolated from women in the assays known in the art; J Gend Specif disorders, cancer. subunit Y54160 follicular phase Med 1999 Nov-Dec; 2(6): 30-4; Mol Cell Endocrinol. 1997 Nov 15; 134(2): 109-18. Follicle stimulating GeneSeq EP974359 FSH stimulates secretion of interleukin-1 FSH activities can be determined using Reproductive system hormone Beta Accession by cells isolated from women in the assays known in the art; J Gend Specif disorders, cancer. subunit Y54161 follicular phase Med 1999 Nov-Dec; 2(6): 30-4; Mol Cell Endocrinol. 1997 Nov 15; 134(2): 109-18. Substance P GeneSeq WO0054053 Substance P is associated with Immuneregulation and bone marrow, cell diabetes mellitus, (tachykinin) Accession immunoregulation. proliferation by substance P can be hypertension, cancer B23027 assayed by methods well-known in the art, for example, Lai et al. Proc Natl Acad Sci USA 2001 Mar 27; 98(7): 3970-5; Jallat- Daloz et al. Allergy Asthma Proc 2001 Jan- Feb; 22(1): 17-23; Kahler et al. Exp Lung Res 2001 Jan-Feb; 27(1): 25-46; and Adamus MA and Dabrowski ZJ. J Cell Biochem 2001; 81(3)499-506. Ocytocin GeneSeq WO0053755 Oxytocin is involved in the induction of Oxytocin and prostaglandin E(2) release inflammatory disorders (Neurophysin I) Accession prostaglandin (E2) release as well as an and Ocytocin (Ca2+) increase can be immunologic disorders, B24085 and increased amount of calcium release by assayed by methods well-known in the art, cancer B24086 smooth muscle cells. for example, Pavan et al., AM J Obset Gynecol 2000 Jul; 183(1): 76-82 and Holda et al., Cell Calcium 1996 Jul; 20(1): 43 51. Vasopressin GeneSeq WO0053755 Vasopressinis believed to have a direct Vasopressin activity can be determined inflammatory disorders (Neurophysin II) Accession antidiuretic action on the kidney, and it is using assays known in the art, for example, immunologic disorders, B24085 and thought to cause vasoconstriction of the Endocr Regul 1996 Mar; 30(I): 13-17. cancer B24086 peripheral vessels. IL-1 GeneSeq EP165654 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, P60326 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Orencole & Dinarclio (1989) Cytokine 1, chemotaxis of neutrophils and T 14-20. lymphocytes, and/or inhibition of interferons. IL-1 mature GeneSeq EP456332 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R14855 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Orencole & Dinarclio (1989) Cytokine 1, chemotaxis of neutrophils and T 14-20. lymphocytes, and/or inhibition of interferons. IL-1 beta GeneSeq WO9922763 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, Y08322 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Orencole & Dinarclio (1989) Cytokine 1, chemotaxis of neutrophils and T 14-20. lymphocytes, and/or inhibition of interferons. IL-3 variants GeneSeq WO8806161 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, P80382, P80383, monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer P80384, and functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, P80381 of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Kitamura et al (1989) J Cell Physiol. 140 chemotaxis of neutrophils and T 323-334. lymphocytes, and/or inhibition of interferons. IL-4 GeneSeq WO8702990 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, P70615 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Siegel & Mostowski (1990) J Immunol chemotaxis of neutrophils and T Methods 132, 287-295. lymphocytes, and/or inhibition of interferons. IL-4 muteins GeneSeq WO9747744 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, W52151 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer W52152 functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, W52153 of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and W52154 cells, eosinophils, and lymphocytes), Siegel & Mostowski (1990) J Immunol W52155 chemotaxis of neutrophils and T Methods 132, 287-295. W52156 lymphocytes, and/or inhibition of W52157 interferons. W52158 W52159 W52160 W52161 W52162 W52163 W52164 and W52165 IL-1 alpha GeneSeq EP324447 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, P90108 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Orencole & Dinarello (1989) Cytokine 1, chemotaxis of neutrophils and T 14-20. lymphocytes, and/or inhibition of interferons. IL-3 variants GeneSeq WO9307171 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R38561, R38562, monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer R38563, R38564, functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, R38565, R38566, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and R38567, R38568, cells, eosinophils, and lymphocytes), Aarden et al (1987) Eur. J. Immunol 17, R38569, R38570, chemotaxis of neutrophils and T 1411-16. R38571, and lymphocytes, and/or inhibition of R38572 interferons. IL-6 GeneSeq WO9402512 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R45717 and monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer R45718 functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Aarden et al (1987) Eur. J. Immunol 17, chemotaxis of neutrophils and T 1411-16. lymphocytes, and/or inhibition of interferons. IL-13 GeneSeq WO9404680 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R48624 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Boutelier et al (1995) J. Immunol. Methods chemotaxis of neutrophils and T 181, 29. lymphocytes, and/or inhibition of interferons. IL-4 mutein GeneSeq DE4137333 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R47182 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Siegel & Mostowski (1990) J Immunol chemotaxis of neutrophils and T Methods 132, 287-295. lymphocytes, and/or inhibition of interferons. IL-4 mutein GeneSeq DE4137333 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Y124X Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R47183 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Siegel & Mostowski (1990) J Immunol chemotaxis of neutrophils and T Methods 132, 287-295. lymphocytes, and/or inhibition of interferons. IL-4 mutein GeneSeq DE4137333 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Y124G Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R47184 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Siegel & Mostowski (1990) J Immunol chemotaxis of neutrophils and T Methods 132, 287-295. lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9317698 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Interleukin-10 Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, (precursor) R41664 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Thompson-Snipes et al (1991) J. Exp. Med. chemotaxis of neutrophils and T 173, 507-510. lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9318783-A Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Interleukin-10 Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R42642 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Thompson-Snipes et al (1991) J. Exp. Med. chemotaxis of neutrophils and T 173, 507-510. lymphocytes, and/or inhibition of interferons. Human GeneSeq EP569042 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, interleukin-1 Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, beta precursor. R42447 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Orencole & Dinarello (1989) Cytokine 1, chemotaxis of neutrophils and T 14-20. lymphocytes, and/or inhibition of interferons. Interleukin- GeneSeq EP578278 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, 1alpha Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R45364 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human GeneSeq JP04063595 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, interleukin-3 Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, variant R22814 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Kitamura et al (1989) J Cell Physiol. 140 chemotaxis of neutrophils and T 323-334. lymphocytes, and/or inhibition of interferons. IL-1i fragments GeneSeq EP541920 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R35484 and monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer R35485 functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Orencole & Dinarclio (1989) Cytokine 1, chemotaxis of neutrophils and T 14-20. lymphocytes, and/or inhibition of interferons. IL-1 inhibitor GeneSeq EPS541920 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, (IL-li) Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R35486 and monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer R35484 functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Orencole & Dinarclio (1989) Cytokine 1, chemotaxis of neutrophils and T 14-20. lymphocytes, and/or inhibition of interferons. ICE 22 kD subunit. GeneSeq EP533350 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R33780 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. ICE 20 kD subunit. GeneSeq EP533350 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R33781 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. ICE 10 kD GeneSeq EP533350 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, subunit Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R33782 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9317698 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Interleukin-10 Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, (precursor) R41664 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Thompson-Snipes et al (1991) J. Exp. Med. chemotaxis of neutrophils and T 173, 507-510. lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9318783 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Interleukin-10 Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R42642 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Thompson-Snipes et al (1991) J. Exp. Med. chemotaxis of neutrophils and T 173, 507-510. lymphocytes, and/or inhibition of interferons. Human GeneSeq EP569042 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Interleukin-1 Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, beta precursor R42447 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Kitamura et al (1989) J Cell Physiol. 140 chemotaxis of neutrophils and T 323-334. lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9403492 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, interleukin-6 Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R49041 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Aarden et al (1987) Eur. J. Immunol 17, chemotaxis of neutrophils and T 1411-16. lymphocytes, and/or inhibition of interferons. Mutant Interleukin 6 GeneSeq WO9411402 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, S176R Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R54990 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Aarden et al (1987) Eur. J. Immunol 17, chemotaxis of neutrophils and T 1411-16. lymphocytes, and/or inhibition of interferons. Interleukin 6 GeneSeq JP06145063 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R55256 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Aarden et al (1987) Eur. J. Immunol 17, chemotaxis of neutrophils and T 1411-16. lymphocytes, and/or inhibition of interferons. Interleukin 8 GeneSeq JP06100595 Interleukins are a group of multifunctional Interleukin activity can be determined using Soluble IL-8 receptor (IL-8) receptor Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in polypeptides may be useful R53932 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical for inhibiting interleukin functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, activities. of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Holmes et al (1991) Science 253, 1278-80. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human GeneSeq U.S. Pat. No. 5,328,988 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, interleukin-7 Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R59919 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Park et al (1990) J. Exp. Med. 171, 1073-79. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. IL-3 containing GeneSeq WO9521254 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, fusion protein. Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R79342 and monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer R79344 functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Kitamura et al (1989) J Cell Physiol. 140 chemotaxis of neutrophils and T 323-334. lymphocytes, and/or inhibition of interferons. IL-3 mutant GeneSeq ZA9402636 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, proteins Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R79254, R79255, monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer R79256, R79257, functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, R79258, R79259, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and R79260, R79261, cells, eosinophils, and lymphocytes), Giri et al (1994) EMBO J. 13 2822-2830. R79262, R79263, chemotaxis of neutrophils and T R79264, R79265, lymphocytes, and/or inhibition of R79266, R79267, interferons. R79268, R79269, R79270, R79271, R79272, R79273, R79274, R79275, R79276, R79277, R79278, R79279, R79280, R79281, R79282, R79283, R79284, and R79285 IL-12 p40 GeneSeq AU9466072 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, subunit. Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R63018 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. AGF GeneSeq WO9429344 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R64240 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9519786 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, interlaukin-12 40 kD Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, subunit R79187 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Hori et al (1987), Blood 70, 1069-1078. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9530695 Interleukins are a group of multifunctional Interleukin activity can be determined using Soluble IL-8 receptor interleukin-15 Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in polypeptides may be useful receptor from R90843 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical for inhibiting interleukin clone P1 functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, activities. of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Giri et al (1994) EMBO J. 13 2822-2830. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9604306 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, interleukin-7 Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R92796 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Park et al (1990) J. Exp. Med. 171, 1073-79. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. interleukin-9 GeneSeq WO9604306 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R92797 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Yang et al (1989) Blood 74, 1880-84. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. interleukin-3 GeneSeq WO9604306 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R92801 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Kitamura et al (1989) J Cell Physiol. 140 chemotaxis of neutrophils and T 323-334. lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9604306 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, interleukin-5 Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, R92802 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Kitamura et al (1989) J Cell Physiol. 140 chemotaxis of neutrophils and T 323-334. lymphocytes, and/or inhibition of interferons. Recombinant GeneSeq DE19617202 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, interleukin-16 Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, W33373 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Lim et al (1996) J. Immunol. 156, 2566-70. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human IL-16 GeneSeq DE19617202 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, protein Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, W33234 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Lim et al (1996) J. Immunol. 156, 2566-70. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Thrl 17 human GeneSeq WO9708321 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, interleukin 9 Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, W27521 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Metl 17 human GeneSeq WO9708321 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, interleukin 9 Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, W27522 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Yang et al (1989) Blood 74, 1880-84. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human GeneSeq EP86-4585 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, intracellular IL-1 Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, receptor W77158 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer antagonist. functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Orencole & Dinarello (1989) Cytokine 1, chemotaxis of neutrophils and T 14-20. lymphocytes, and/or inhibition of interferons. Human GeneSeq EP864585 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, interleukin-18 Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, protein (IL-18) W77158 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), USHIO et al (1996) J. Immunol. 156, 4274-79. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human GeneSeq EP861663 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, interleukin-18 Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., in immunologic disorders, W77077 monocytes, and macrophages. Known Lymphokines and Interferens: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), USHIO et al (1996) J. Immunol. 156, 4274-79. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human interleukin GeneSeq EP861663 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, 18 derivatives Accessions cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., immunologic disorders, W77083, monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical cancer W77084, functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, W77085, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and W77086, cells, eosinophils, and lymphocytes), Ushio et al (1996) J. Immunol, 156, 4274-79. W77087, chemotaxis of neutrophils and T W77088, and lymphocytes, and/or inhibition of W77089 interferons. Interleukin-9 GeneSeq WO9827997 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, (IL-9) mature Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., immunologic disorders, protein (Thr117 W68158 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical cancer version). functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Yang et al (1989) Blood 74, 1880-84. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. IL-9 mature GenSeq Accession WO9827997 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, protein variant W68157 cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., immunologic disorders, (Met117 version) monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Yang et al (1989) Blood 74, 1880-84. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human IL-9 GeneSeq WO9824904 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, receptor protein Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., immunologic disorders, variant #3. W64058 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Yang et al (1989) Blood 74, 1880-84. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human IL-9 GenSeq Accession WO9824904 Interleukins are a group of multifunctional Interleukin activity can be determined using Soluble IL-9 receptor receptor protein W64060 cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., polypeptides may be useful variant fragment monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical for inhibiting interleukin functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, activities. of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Yang et al (1989) Blood 74, 1880-84. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human IL-9 GeneSeq WO9824904 Interleukins are a group of multifunctional Interleukin activity can be determined using Soluble IL-9 receptor receptor protein Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., polypeptides may be useful variant #3. W64061 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical for inhibiting interleukin functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, activities. of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Yang et al (1989) Blood 74, 1880-84. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9817689 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Interleukin-12 p40 Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., immunologic disorders, protein W51311 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Hori et al (1987), Blood 70, 1069-1078. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9817689 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Interleukin-12 p35 Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., immunologic disorders, protein W51312 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Hori et al (1987), Blood 70, 1069-1078. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human protein GeneSeq DE19649233- Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, with IL-16 activity Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., immunologic disorders, W63753 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Lim et al (1996) J. Immunol. 156, 2566-70. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human protein GeneSeq DE19649233- Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, with IL-16 activity Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., immunologic disorders, W59425 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Lim et al (1996) J. Immunol. 156, 2566-70. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human GeneSeq U.S. Pat. No. 5,747,024 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, interleukin-15 Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., immunologic disorders, W53878 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Giri et al (1994) EMBO J. 13 2822-2830. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human wild-type GeneSeq WO9747744 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, interleukin-4 (hIL- Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., immunologic disorders, 4) protein W52149 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Siegel & Mostowski (1990) J Immunol chemotaxis of neutrophils and T Methods 132, 287-295. lymphocytes, and/or inhibition of interferons. interleukin-4 GeneSeq WO9747744 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, muteins Accessions cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., immunologic disorders, W52150, monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical cancer W52151, functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, W52153, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and W52154, cells, eosinophils, and lymphocytes), Siegel & Mostowski (1990) J Immunol W52155, chemotaxis of neutrophils and T Methods 132, 287-295. W52156, lymphocytes, and/or inhibition of W52157, interferons. W52158, W52159, W52160, W52161, W52162, W52163, W52164, W52165, W52166, and W52167 Human interleukin GeneSeq WO9935268 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, 1 delta Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., immunologic disorders, Y28408 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Orencole & Dinarello (1989) Cytokine 1, chemotaxis of neutrophils and T 14-20. lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9935268 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, interleukin-1 Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., immunologic disorders, receptor Y24395 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical cancer antagonist beta functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Orencole & Dinarello (1989) Cytokine 1, chemotaxis of neutrophils and T 14-20. lymphocytes, and/or inhibition of interferons. Human EDIRF II GeneSeq WO9932632 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, protein sequence Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., immunologic disorders, Y22199 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human EDIRF I GeneSeq WO9932632 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, protein sequence Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., immunologic disorders, Y22197 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human IL-1RD10 GeneSeq WO9919480 Interleukins are a group of multifunctional Interleukin activity can be determined using Soluble IL-1RD10 receptor protein sequence Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., polypeptides may be useful Y14131 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical for inhibiting interleukin functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, activites. of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Orencole & Dinarello (1989) Cytokine 1, chemotaxis of neutrophils and T 14-20. lymphocytes, and/or inhibition of interferons. Human IL-1RD9 GeneSeq WO9919480 Interleukins are a group of multifunctional Interleukin activity can be determined using Soluble IL-1RD10 receptor Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., polypeptides may be useful Y14122 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical for inhibiting interleukin functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, activites. of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Orencole & Dinarello (1989) Cytokine 1, chemotaxis of neutrophils and T 14-20. lymphocytes, and/or inhibition of interferons. Human DNAX GeneSeq WO9919491 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, interleukin-40 Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., immunologic disorders, Y09196 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. (DIL-40) GeneSeq WO9919491 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, alternative Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., immunologic disorders, sequence Y09197 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. IL-11 GeneSeq WO9405318 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., immunologic disorders, R50176 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Lu et al (1994) J immunol. Methods 173, chemotaxis of neutrophils and T 19. lymphocytes, and/or inhibition of interferons. Human GeneSeq EP566410 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, adipogenesis Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., immunologic disorders, inhibitory factor R43260 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. IL-11 GeneSeq JP08127539 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., immunologic disorders, W02202 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Lu et al (1994) J immunol. Methods 173, chemotaxis of neutrophils and T 19. lymphocytes, and/or inhibition of interferons. IL-14 GeneSeq WO9416074 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., immunologic disorders, R55800 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Ambrus et al (1993) PNAS 90, 63330-34. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. IL-17 receptor GeneSeq U.S. Pat. No. 6,072,033 Interleukins are a group of multifunctional Interleukin activity can be determined using Soluble IL-17 receptor Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., polypeptides may be useful B03807 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical for inhibiting interleukin functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, activities. of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Yao et al (1995) J. Immunol. 155, 5483-86. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. IL-17 GeneSeq WO9518826 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., immunologic disorders, R76573 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Yao et al (1995) J. Immunol. 155, 5483-86. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. CTLA-8 GeneSeq WO9704097 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., immunologic disorders, W13651 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. IL-19 GeneSeq WO9808870 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., immunologic disorders, W37935 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Gallagher et al (2000) Genes Immun. 1, chemotaxis of neutrophils and T 442-50. lymphocytes, and/or inhibition of interferons. IL-21 (TIF) GeneSeq WO0024758 Interleukins are a group of multifunctional Interleukin activity can be determined using inflammatory disorders, Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., immunologic disorders, Y92879 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical cancer functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Parrish-Novak et al (2000) Nature 408, 57-63. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. IL-8 receptor GeneSeq WO9306229 Interleukins are a group of multifunctional Interleukin activity can be determined using Soluble IL-8 receptor Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., polypeptides may be useful R33420 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical for inhibiting interleukin functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, activities. of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Holmes et al (1991) Science 253, 1278-80.. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human type II GeneSeq U.S. Pat. No. 5,464,937 Interleukins are a group of multifunctional Interleukin activity can be determined using Soluble type II interleukin-1 interleukin-1 Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., receptor polypeptides may receptor R85480 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical be useful for inhibiting functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, interleukin activities. of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Orencole & Dinarello (1989) Cytokine 1, chemotaxis of neutrophils and T 14-20. lymphocytes, and/or inhibition of interferons. Human GeneSeq EP638644 Interleukins are a group of multifunctional Interleukin activity can be determined using Soluble IL-12 receptor interleukin-12 Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., polypeptides may be useful receptor R69632 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical for inhibiting interleukin functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, activities. of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Hori et al (1987), Blood 70, 1069-1078. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Interleukin 8 GeneSeq U.S. Pat. No. 5,440,021 Interleukins are a group of multifunctional Interleukin activity can be determined using Soluble IL-8 receptor B receptor B Accession cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., polypeptides may be useful R80758 monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical for inhibiting interleukin functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, activities. of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Holmes et al (1991) Science 253, 1278-80. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human IL-8 GeneSeq JP08103276 Interleukins are a group of multifunctional Interleukin activity can be determined using Soluble IL-8 receptor A receptor protein Accession B09989 cytokines synthesized by lymphocytes, assays known in the art: Matthews et al., polypeptides may be useful hIL8RA monocytes, and macrophages. Known in Lymphokines and Interferons: A Practical for inhibiting interleukin functions include stimulating proliferation Approach, Clemens et al., eds, IRL Press, activities. of immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Holmes et al (1991) Science 253, 1278-80. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human IL-8 GeneSeq JP08103276 Interleukins are a group of multifunctional Interleukin activity can be determined Soluble IL-8 receptor receptor protein Accession B09990 cytokines synthesized by lymphocytes, using asays known in the art: Matthews et polypeptides may be hIL8R monocytes, and macrophages. Known al., in Lymphokines and Interferons: A useful for inhibiting functions include stimulating proliferation Practical Approach, Clemens et al., eds, interleukin activities. of immune cells (e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes), 221-225; and Holmes et al (1991) Science chemotaxis of neutrophils and T 253, 1278-80. lymphocytes, and/or inhibition of interferons. Interleukin-2 GeneSeq WO9621732- Interleukins are a group of multifunctional Interleukin activity can be determined Soluble IL-2 receptor receptor Accession cytokines synthesized by lymphocytes, using assays known in the art: Matthews polypeptides may be associated protein R97569 monocytes, and macrophages. Known et al., in Lymphokines and Interferons: A useful for inhibiting p43 functions include stimulating proliferation Practical Approach, Clemens et al., eds, interleukin activities. of immune cells (e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes), 221-225; and Gillis et al (1978) J. chemotaxis of neutrophils and T Immunol. 120, 2027. lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9629408 Interleukins are a group of multifunctional Interleukin activity can be determined Soluble IL-17 receptor interleukin-17 Accession cytokines synthesized by lymphocytes, using assays known in the art: Matthews polypeptides may be receptor W04185 monocytes, and macrophages. Known et al., in Lymphokines and Interferons: A useful for inhibiting functions include stimulating proliferation Practical Approach, Clemens et al., eds, interleukin activities. of immune cells (e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes), 221-225; and Yao et al (1995) J. Immunol. chemotaxis of neutrophils and T 155, 5483-86. lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9619574 Interleukins are a group of multifunctional Interleukin activity can be determined Soluble IL-11 receptor interleukin-11 Accession cytokines synthesized by lymphocytes, using assays known in the art: Matthews polypeptides may be receptor R99090 monocytes, and macrophages. Known et al., in Lymphokines and Interferons: A useful for inhibiting functions include stimulating proliferation Practical Approach, Clemens et al., eds, interleukin activities. of immune cells (e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes), 221-225; and Lu et al (1994) J immunol. chemotaxis of neutrophils and T Methods 173, 19. lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9623067 Interleukins are a group of multifunctional Interleukin activity can be determined Inflammatory disorders, interleukin-1 Accession cytokines synthesized by lymphocytes, using assays known in the art: Matthews immunologic disorders, receptor W01911 monocytes, and macrophages. Known et al., in Lymphokines and Interferons: A cancer accessory protein functions include stimulating proliferation Practical Approach, Clemens et al., eds, of immune cells (e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes), 221-225; and Orencole & Dinarello (1989) chemotaxis of neutrophils and T Cytokine 1, 14-20. lymphocytes, and/or inhibition of interferons. AGF Protein GeneSeq U.S. Pat. No. 5,488,032 Interleukins are a group of multifunctional Interleukin activity can be determined Inflammatory disorders, Accession cytokines synthesized by lymphocytes, using assays known in the art: Matthews immunologic disorders, R92749 monocytes, and macrophages. Known et al., in Lymphokines and Interferons: A cancer functions include stimulating proliferation Practical Approach, Clemens et al., eds, of immune cells (e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes), 221-225. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human GeneSeq W09607739 Interleukins are a group of multifunctional Interleukin activity can be determined Soluble IL-type-3 receptor interleukin-1 type- Accession cytokines synthesized by lymphocytes, using assays known in the art: Matthews polypeptides may be 3 receptor R91064 monocytes, and macrophages. Known et al., in Lymphokines and Interferons: A useful for inhibiting functions include stimulating proliferation Practical Approach, Clemens et al., eds, interleukin activities of immune cells (e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes), 221-225; and Orencole & Dinarello (1989) chemotaxis of neutrophils and T Cytokine 1, 14-20. lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9720926 Interleukins are a group of multifunctional Interleukin activity can be determined Soluble IL-13 beta interleukin-13 beta Accession cytokines synthesized by lymphocytes, using assays known in the art: Matthews receptor polypeptides may receptor W24972 monocytes, and macrophages. Known et al., in Lymphokines and Interferons: A be useful for inhibiting functions include stimulating proliferation Practical Approach, Clemens et al., eds, interleukin activities. of immune cells (e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes), 221-225; and Boutelier et al (1995) J. chemotaxis of neutrophils and T Immunol. Methods 181, 29. lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9720926 Interleukins are a group of multifunctional Interleukin activity can be determined Soluble IL-13 alpha interleukin-13 Accession cytokines synthesized by lymphocytes, using assays known in the art: Matthews receptor polypeptides may alpha receptor W24973 monocytes, and macrophages. Known et al., in Lymphokines and Interferons: A be useful for inhibiting functions include stimulating proliferation Practical Approach, Clemens et al., eds, interleukin activities. of immune cells (e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes), 221-225; and Boutelier et al (1995) J. chemotaxis of neutrophils and T Immunol. Methods 181, 29. lymphocytes, and/or inhibition of interferons. Human GeneSeq U.S. Pat. No. 5,599,905 Interleukins are a group of multifunctional Interleukin activity can be determined Soluble IL-4 receptor interleukin-4 Accession cytokines synthesized by lymphocytes, using assays known in the art: Matthews polypeptides may be receptor W13499 monocytes, and macrophages. Known et al., in Lymphokines and Interferons: A useful for inhibiting functions include stimulating proliferation Practical Approach, Clemens et al., eds, interleukin activities. of immune cells (e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes), 221-225; and Siegel & Mostowski (1990) J chemotaxis of neutrophils and T Immunol Methods 132, 287-295. lymphocytes, and/or inhibition of interferons. Human GeneSeq EP759466 Interleukins are a group of multifunctional Interleukin activity can be determined Soluble IL-12 beta-2 interleukin-12 Accession cytokines synthesized by lymphocytes, using assays known in the art: Matthews receptor polypeptides may beta-2 receptor W12771 monocytes, and macrophages. Known et al., in Lymphokines and Interferons: A be useful for inhibiting functions include stimulating proliferation Practical Approach, Clemens et al., eds, interleukin activities. of immune cells (e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes), 221-225; and Hori et al (1987), Blood 70, chemotaxis of neutrophils and T 1069-1078. lymphocytes, and/or inhibition of interferons. Human GeneSeq EP759466 Interleukins are a group of multifunctional Interleukin activity can be determined Soluble IL-12 beta-1 interleukin-12 Accession cytokines synthesized by lymphocytes, using assays known in the art: Matthews receptor polypeptides may beta-1 receptor. W12772 monocytes, and macrophages. Known et al., in Lymphokines and Interferons: A be useful for inhibiting functions include stimulating proliferation Practical Approach, Clemens et al., eds, interleukin activities. of immune cells (e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes), 221-225; and Hori et al (1987), Blood 70, chemotaxis of neutrophils and T 1069-1078. lymphocytes, and/or inhibition of interferons. Human IL-9 GeneSeq WO9824904 Interleukins are a group of multifunctional Interleukin activity can be determined Soluble IL-9 receptor receptor protein Accessions cytokines synthesized by lymphocytes, using assays known in the art: Matthews polypeptides may be W64055, W64056, monocytes, and macrophages. Known et al., in Lymphokines and Interferons: A useful for inhibiting and W64057 functions include stimulating proliferation Practical Approach, Clemens et al., eds, interleukin activities. of immune cells (e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes), 221-225; and Yang et al (1989), Blood 74, chemotaxis of neutrophils and T 1880-84.. lymphocytes, and/or inhibition of interferons. IL-10 receptor GeneSeq U.S. Pat. No. 5,716,804 Interleukins are a group of multifunctional Interleukin activity can be determined Soluble IL-10 receptor Accession cytokines synthesized by lymphocytes, using assays known in the art: Matthews polypeptides may be W41804 monocytes, and macrophages. Known et al., in Lymphokines and Interferons: A useful for inhibiting functions include stimulating proliferation Practical Approach, Clemens et al., eds, interleukin activities. of immune cells (e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes), 221-225; and Thompson-Snipes et al chemotaxis of neutrophils and T (1991) J. Exp. Med. 173, 507-510. lymphocytes, and/or inhibition of interferons. Human IL-6 GeneSeq JP11196867 Interleukins are a group of multifunctional Interleukin activity can be determined Soluble IL-6 receptor receptor Accession Y30938 cytokines synthesized by lymphocytes, using assays known in the art: Matthews polypeptides may be monocytes, and macrophages. Known et al., in Lymphokines and Interferons: A useful for inhibiting functions include stimulating proliferation Practical Approach, Clemens et al., eds, interleukin activities. of immune cells (e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes), 221-225; and Aarden et al (1987) Eur. J. chemotaxis of neutrophils and T Immunol 17, 1411-16. lymphocytes, and/or inhibition of interferons. Il-17 receptor GeneSeq U.S. Pat. No. 6,096,305 Interleukins are a group of multifunctional Interleukin activity can be determined Soluble IL-17 receptor Accession Y97181 cytokines synthesized by lymphocytes, using assays known in the art: Matthews polypeptides may be monocytes, and macrophages. Known et al., in Lymphokines and Interferons: A useful for inhibiting functions include stimulating proliferation Practical Approach, Clemens et al., eds, interleukin activities. of immune cells (e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes), 221-225; and Yao et al (1995) J. Immunol. chemotaxis of neutrophils and T 155, 5483-86. lymphocytes, and/or inhibition of interferons. Il-17 receptor GeneSeq U.S. Pat. No. 6,100,235 Interleukins are a group of multifunctional Interleukin activity can be determined Soluble IL-17 receptor Accession Y97131 cytokines synthesized by lymphocytes, using assays known in the art: Matthews polypeptides may be monocytes, and macrophages. Known et al., in Lymphokines and Interferons: A useful for inhibiting functions include stimulating proliferation Practical Approach, Clemens et al., eds, interleukin activities. of immune cells (e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes), 221-225; and Yao et al (1995) J. Immunol. chemotaxis of neutrophils and T 155, 5483-86. lymphocytes, and/or inhibition of interferons. Human GeneSeq EP509826 Interleukins are a group of multifunctional Interleukin activity can be determined Soluble IL-3 receptor interleukin-3 Accession cytokines synthesized by lymphocytes, using assays known in the art: Matthews polypeptides may be receptor R25300 monocytes, and macrophages. Known et al., in Lymphokines and Interferons: A useful for inhibiting functions include stimulating proliferation Practical Approach, Clemens et al., eds, interleukin activities. of immune cells (e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes), 221-225; and Kitamura et al (1989) J Cell chemotaxis of neutrophils and T Physiol. 140 323-334. lymphocytes, and/or inhibition of interferons. Human GM-CSF GeneSeq WO9102063 Interleukins are a group of multifunctional Interleukin activity can be determined Soluble GM-CSF receptor receptor Accession cytokines synthesized by lymphocytes, using assays known in the art: Matthews polypeptides may be R10919 monocytes, and macrophages. Known et al., in Lymphokines and Interferons: A useful for inhibiting functions include stimulating proliferation Practical Approach, Clemens et al., eds, interleukin activities. of immune cells (e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes), 221-225. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human IL-5 GeneSeq EP492214 Interleukins are a group of multifunctional Interleukin activity can be determined Soluble IL-5 receptor receptor alpha Accession cytokines synthesized by lymphocytes, using assays known in the art: Matthews alpha polypeptides may be chain R25064 monocytes, and macrophages. Known et al., in Lymphokines and Interferons: A useful for inhibiting functions include stimulating proliferation Practical Approach, Clemens et al., eds, interleukin activities. of immune cells (e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes), 221-225; and Kitamura et al (1989) J Cell chemotaxis of neutrophils and T Physiol. 140, 323-334. lymphocytes, and/or inhibition of interferons. II-5 receptor GeneSeq WO9847923 Interleukins are a group of multifunctional Interleukin activity can be determined Soluble IL-5 receptor Accession cytokines synthesized by lymphocytes, using assays known in the art: Matthews polypeptides may be W82842 monocytes, and macrophages. Known et al., in Lymphokines and Interferons: A useful for inhibiting functions include stimulating proliferation Practical Approach, Clemens et al., eds, interleukin activities. of immune cells (e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes), 221-225; and Kitamura et al (1989) J Cell chemotaxis of neutrophils and T Physiol. 140, 323-334. lymphocytes, and/or inhibition of interferons. II-6 receptor GeneSeq JP05091892 Interleukins are a group of multifunctional Interleukin activity can be determined Soluble IL-6 receptor Accession cytokines synthesized by lymphocytes, using assays known in the art: Matthews polypeptides may be R37215 monocytes, and macrophages. Known et al., in Lymphokines and Interferons: A useful for inhibiting functions include stimulating proliferation Practical Approach, Clemens et al., eds, interleukin activities. of immune cells (e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes), 221-225; and Aarden et al (1987) Eur. J. chemotaxis of neutrophils and T Immunol 17, 1411-16. lymphocytes, and/or inhibition of interferons. Human B cell GeneSeq AU8928720 Interleukins are a group of multifunctional Interleukin activity can be determined Soluble B cell stimulating stimulating factor- Accession P90525 cytokines synthesized by lymphocytes, using assays known in the art: Matthews factor-2 receptor 2 receptor monocytes, and macrophages. Known et al., in Lymphokines and Interferons: A polypeptides may be functions include stimulating proliferation Practical Approach, Clemens et al., eds, useful for inhibiting of immune cells (e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. interleukin activities. cells, eosinophils, and lymphocytes), 221-225. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. IL-7 receptor GeneSeq EP403114 Interleukins are a group of multifunctional Interleukin activity can be determined Soluble IL-7 receptor clone Accession cytokines synthesized by lymphocytes, using assays known in the art: Matthews polypeptides may be R08330 monocytes, and macrophages. Known et al., in Lymphokines and Interferons: A useful for inhibiting functions include stimulating proliferation Practical Approach, Clemens et al., eds, interleukin activities. of immune cells (e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes), 221-225; and Park et al (1990) J. Exp. chemotaxis of neutrophils and T Med. 171, 1073-79. lymphocytes, and/or inhibition of interferons. EPO receptor; GeneSeq WO9008822 EPO Receptor is involved in the EPO Receptor activity can be determined Inflammatory disorders, EPOR Accession proliferation and differentiation of using assays known in the art, such as, J immunologic disorders, R06512 erythroblasts. Biol Chem 2001 Mar 23; 276(12: 8995-9002; cancer, erythroblast JAK2 protein tyrosine kinase proliferation and activity: Blood 1994 Sep 1; 84(5): 1501-7 differentiation and Mol Cell Biol. 1994 Oct; 14(10: 6506-14. IL-15 receptor GeneSeq WO9530695 Interleukins are a group of multifunctional Interleukin activity can be determined Soluble IL-15 receptor Accession cytokines synthesized by lymphocytes, using assays known in the art: Matthews polypeptides may be R90843 monocytes, and macrophages. Known et al., in Lymphokines and Interferons: A useful for inhibiting functions include stimulating proliferation Practical Approach, Clemens et al., eds, interleukin activities. of immune cells (e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes), 221-225; and Giri et al (1994) EMBO J. 13 chemotaxis of neutrophils and T 2822-2830. lymphocytes, and/or inhibition of interferons. CD137; 4-1BB GeneSeq WO9507984 Activities associated with apoptosis, NF- Apoptosis activity, NF-kB activation, and B Soluble 4-1BB receptor Receptor Protein Accession kB activation, and co-stimulation of and T cell co-stimulation can be polypeptides may be R70977 immune cells such as T and B cells. determined using assays known in the art: useful for inhibiting Moore et al., 1999, Science, apoptosis, NF-kB 285(5425): 260-3; Song HY et al., 1997 activation, and/or co- Proc Natl Acad Sci USA 94(18): 9792-6; stimulation of immune Epsevik and Nissen-Meyer, 1986, J. cells such as B and T Immunol. Methods. cells. BCMA GeneSeq WO0068378 Activities associated with apoptosis, NF- Apoptosis activity, NF-kB activation, and B Soluble BCMA receptor Accession Y71979 kB activation, and co-stimulation of and T cell co-stimulation can be polypeptides may be immune cells such as T and B cells. determined using assays known in the art: useful for inhibiting Moore et al., 1999, Science, apoptosis, NF-kB 285(5425): 260-3; Song HY et al., 1997 activation, and/or co- Proc Natl Acad Sci USA 94(18): 9792-6; stimulation of immune Epsevik and Nissen-Meyer, 1986, J. cells such as B and T Immunol. Methods. cells. CD27 GeneSeq WO9201049 Activities associated with apoptosis, NF- Apoptosis activity, NF-kB activation, and B Soluble CD27 Accession kB activation, and co-stimulation of and T cell co-stimulation can be polypeptides may be R20814 immune cells such as T and B cells. determined using assays known in the art: useful for inhibiting Moore et al., 1999, Science, apoptosis, NF-kB 285(5425): 260-3; Song HY et al., 1997 activation, and/or co- Proc Natl Acad Sci USA 94(18): 9792-6; stimulation of immune Epsevik and Nissen-Meyer, 1986, J. cells such as B and T Immunol. Methods. cells. CD30 GeneSeq DE4200043 Activities associated with apoptosis, NF- Apoptosis activity, NF-kB activation, and B Soluble CD30 Accession kB activation, and co-stimulation of and T cell co-stimulation can be polypeptides may be R35478 immune cells such as T and B cells. determined using assays known in the art: useful for inhibiting Moore et al., 1999, Science, apoptosis, NF-kB 285(5425): 260-3; Song HY et al., 1997 activation, and/or co- Proc Natl Acad Sci USA 94(18): 9792-6; stimulation of immune Epsevik and Nissen-Meyer, 1986, J. cells such as B and T Immunol. Methods. cells. CD40 GeneSeq WO9945944 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, and B Soluble CD40 Accession NF-kB activation, and co-stimulation of and T cell co-stimulation can be polypeptides may be Y33499 immune cells such as T and B cells. determined using assays known in the art: useful for inhibiting Moore et al., 1999, Science apoptosis, NF-kB 285(5425): 260-3; Song HY et al., 1997 activation, and/or co- Proc Natl Acad Sci USA 94(18): 9792-6; stimulation of immune Epsevik and Nissen-Meyer, 1986, J. cells such as B and T Immunol. Methods. cells. EDAR Genbank Activities associated with apoptosis, Apoptosis activity, NF-kB activation, and B Immune Disorders, Accession NF-kB activation, and co-stimulation of and T cell co-stimulation can be Lymphomas, X-linked AAD50077 immune cells such as T and B cells. determined using assays known in the art: hypohidrotic ectodermal Moore et al., 1999, Science, dysplasia 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. OX40; ACT-4 GeneSeq WO9512673 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, and B Immune Disorders, Accession R74737 NF-kB activation, and co-stimulation of and T cell co-stimulation can be Lymphomas, T cell immune cells such as T and B cells. determined using assays known in the art: disorders Moore et al., 1999, Science, 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. TACI GeneSeq WO9839361 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, and B Soluble TACI receptor Accession NF-kB activation, and co-stimulation of and T cell co-stimulation can be polypeptides may be W75783 immune cells such as T and B cells. determined using assays known in the art: useful for inhibiting Moore et al., 1999, Science, apoptosis, NF-kB 285(5425): 260-3; Song HY et al., 1997 activation, and/or co- Proc Natl Acad Sci USA 94(18): 9792-6; stimulation of immune Epsevik and Nissen-Meyer, 1986, J. cells such as B and T Immunol. Methods. cells. TNF-R GeneSeq AU9058976 Activities associates with apoptosis, Apoptosis activity, NF-kB activation, and B Soluble TNF-R receptor Accession R10986 NF-kB activation, and co-stimulation of and T cell co-stimulation can be polypeptides may be immune cells such as T and B cells. determined using assays known in the art: useful for inhibiting Moore et al., 1999, Science, apoptosis, NF-kB 285(5425): 260-3; Song HY et al., 1997 activation, and/or co- Proc Natl Acad Sci USA 94(18): 9792-6; stimulation of immune Epsevik and Nissen-Meyer, 1986, J. cells such as B and T Immunol. Methods. cells. TNF-RII; TNF GeneSeq EP418014 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, and B Soluble TNFR-II receptor p75 receptor; Accession R11141 NF-kB activation, and co-stimulation of and T cell co-stimulation can be polypeptides may be Death Receptor immune cells such as T and B cells. determined using assays known in the art: useful for inhibiting Moore et al., 1999, Science, apoptosis, NF-kB 285(5425): 260-3; Song HY et al., 1997 activation, and/or co- Proc Natl Acad Sci USA 94(18)9792-6; stimulation of immune Epsevik and Nissen-Meyer, 1986, J. cells such as B and T Immunol. Methods. cells. hAPO-4; TROY GeneSeq WO9911791 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, and B Immune Disorders, Accession NF-kB activation, and co-stimulation of and T cell co-stimulation can be Cancers W93581 immune cells such as T and B cells. determined using assays known in the art: Moore et al., 1999, Science, 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. TNF-alpha GeneSeq EP205038 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, and B Inflammatory disorders, precursor Accession P60074 NF-kB activation, and co-stimulation of and T cell co-stimulation can be immunologic disorders, immune cells such as T and B cells. determined using assays known in the art: cancer Moore et al., 1999, Science, 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. Human TNF- GeneSeq EP619372 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, and B Inflammatory disorders, alpha Accession R62463 NF-kB activation, and co-stimulation of and T cell co-stimulation can be immunologic disorders, immune cells such as T and B cells determined using assays known in the art: cancer Moore et al., 1999, Science, 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. Human TNF- GeneSeq EP563714 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, and B Inflammatory disorders, alpha Accession R42679 NF-kB activation, and co-stimulation of and T cell co-stimulation can be immunologic disorders, immune cells such as T and B cells. determined using assays known in the art: cancer Moore et al., 1999, Science, 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. Human TNF- GeneSeq WO0064479 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, and B Inflammatory disorders, beta (LT-alpha) Accession B37799 NF-kB activation, and co-stimulation of and T cell co-stimulation can be immunologic disorders, immune cells such as T and B cells. determined using assays known in the art: cancer Moore et al., 1999, Science, 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. LT-alpha GeneSeq EP250000 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, and B Inflammatory disorders, Accession P70107 NF-kB activation, and co-stimulation of and T cell co-stimulation can be immunologic disorders, immune cells such as T and B cells. determined using assays known in the art: cancer Moore et al., 1999, Science, 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. LT-beta GeneSeq WO9413808 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, and B Inflammatory disorders, Accession R56869 NF-kB activation, and co-stimulation of and T cell co-stimulation can be immunologic disorders, immune cells such as T and B cells. determined using assays known in the art: cancer Moore et al., 1999, Science, 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18)9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. OPGL GeneSeq WO9846751 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, and B Inflammatory disorders, Accession NF-kB activation, and co-stimulation of and T cell co-stimulation can be immunologic disorders, W83195 immune cells such as T and B cells. determined using assays known in the art: cancer, loss of bone mass Moore et al., 1999, Science, 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18)9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. FasL GeneSeq WO9903999 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, and B Inflammatory disorders, Accession NF-kB activation, and co-stimulation of and T cell co-stimulation can be immunologic disorders, W98071 immune cells such as T and B cells. determined using assays known in the art: cancer Moore, et al., 1999, Science, 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18)9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. FasL GeneSeq WO9903998 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, and B Inflammatory disorders, Accession NF-kB activation, and co-stimulation of and T cell co-stimulation can be imunologic disorders, W95041 immune cells such as T and B cells. determined using assays known in the art: cancer Moore et al., 1999, Science, 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. CD27L GeneSeq WO9405691 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, and B Inflammatory disorders, Accession R50121 NF-kB activation, and co-stimulation of and T cell co-stimulation can be immunologic disorders, immune cells such as T and B cells. determined using assays known in the art: cancer Moore et al., 1999, Science, 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. CD30 ligand GeneSeq WO9324135 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, and B Inflammatory disorders, Accession R45007 NF-kB activation, and co-stimulation of and T cell co-stimulation can be immunologic disorders, immune cells such as T and B cells. determined using assays known in the art: cancer Moore et al., 1999, Science, 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. CD40L GeneSeq WO9529935 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, and B Inflammatory disorders, Accession R85486 NF-kB activation, and co-stimulation of and T cell co-stimulation can be immunologic disorders, immune cells such as T and B cells. determined using assays known in the art: cancer Moore, et al., 1999, Science, 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. 4-1BB ligand GeneSeq U.S. Pat. No. 5,674,704 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, and B Inflammatory disorders, Accession NF-kB activation, and co-stimulation of and T cell co-stimulation can be immunologic disorders, W26657 immune cells such as T and B cells. determined using assays known in the art: cancer Moore et al., 1999, Science, 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. FAS Ligand GeneSeq WO0058465 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, and B Soluble DcR3 Inhibitory Accession B19335 NF-kB activation, and co-stimulation of and T cell co-stimulation can be polypeptides may be Protein (DcR3) immune cells such as T and B cells. determined using assays known in the art: useful for inhibiting Moore et al., 1999, Science, apoptosis, NF-kB 285(5425): 260-3; Song HY et al., 1997 activation, and/or co- Proc Natl Acad Sci USA 94(18): 9792-6; stimulation of immune Epsevik and Nissen-Meyer, 1986, J. cells such as B and T Immunol. Methods cells. OX40L GeneSeq WO9521915 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, and B Inflammatory disorders, Accession R79903 NF-kB activation, and co-stimulation of and T cell co-stimulation can be immunologic disorders, immune cells such as T and B cells. determined using assays known in the art: cancer Moore et al., 1999, Science, 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. Protease GeneSeq WO9106561 Peptides that inhibit the function/binding HIV protease activities are known in the art: HIV, inflammatory inhibitor Accessions of HIV HIV protease assays: EP0387231. One disorders, immunologic peptides R12435, R12436, can modify the assay to look for inhibition disorders, cancer, viral R12437, R12438, using any of the disclosed protease infections R12439, R12440, inhibitor polypeptides. and R1244 Retroviral GeneSeq EP387231 Peptides that inhibit the function/binding HIV protease activities are known in the art: HIV, inflammatory protease Accessions of HIV HIV protease assays: EP0387231. One disorders, immunologic inhibitors R06660, R06661, can modify the assay to look for inhibition disorders, cancer, viral R06662, R06663, using any of the disclosed protease infections R06664, R06665, inhibitor polypeptides. R06666, R06667, R06668, R06669, R06670, R06671, R06672, R06673, R06674, R06675, and R06676 HIV protease GeneSeq WO9301828 Peptides that inhibit the function/binding HIV protease activities are known in the art: HIV, inflammatory inhibiting Accessions of HIV HIV protease assays: EP0387231. One disorders, immunologic peptides R59293, R59294, can modify the assay to look for inhibition disorders, cancer, viral R59295, R59296, using any of the disclosed protease infections R59297, inhibitor polypeptides. R59298, R59299, R592300, R59301, R59302, R59301, R59302, R59303, R59304, R59305, R59306, R59307, R59308, R59309, R59310, R59311, R59312, R59313, R59314, R59315, R59316, R59317 R59318, R59319, R59320, R59321, R59322, R59323, R59324, R59325, R59326, R59327, R59328, R59329, R59330, R59331, R59332, R59333, R59334, R59335, R59336, R59337, R59338, R59339, R59340, R59341, R59342, R59343, R59344, R59345, R59346, R59347, R59348, R59349, and R59350 HIV-1 protease GeneSeq DE4412174 Peptides that inhibit the function/binding HIV protease activities are known in the art: HIV, inflammatory hinibitors Accessions of HIV HIV protease assays: EP0387231. One disorders, immunologic R86326, R86327, can modify the assay to look for inhibition disorders, cancer, viral R86328, R86329, using any of the disclosed protease infections R86330, R86331, inhibitor polypeptides. R86332, R86333, R86334, R86335, R86336, R86337, R86338, R86339, R86340, R86341, R86342, R86343, R86344, R86345, R86346, R86347, R86348, R86349, R86350, R86351, R86352, R86353, R86354, R86355, R86356, R86357, R86358, R86359, R86360, R86361, R86362, R86363, R86364, R86365, R86366, R86367, R86368, R86369, R86370, and R86371 HIV Inhibitor GeneSeq WO9959615 Peptides that inhibit the function/binding HIV protease activities are known in the art: HIV, inflammatory Peptide Accession of HIV HIV protease assays: EP0387231. One disorders, immunologic Y89687 can modify the assay to look for inhibition disorders, cancer, viral using any of the disclosed protease infections inhibitor polypeptides. HIV Inhibitor GenSeq WO9948513 Peptides that inhibit the function/binding HIV Protease activities are known in the HIV, inflammatory Peptide Accession Y31955 of HIV art; HIV protease assays: EP0387231. disorders, immunologic One can modify the assay to look for disorders, cancer, viral inhibition using any of the disclosed infections. protease inhibitor polypeptides. HIV Inhibitor www.sciencexpress.org; Peptides that inhibit the function/binding HIV protease activities are known in the HIV, inflammatory Peptide Published of HIV art: HIV protease assays: EP0387231. disorders, immunologic online 12 Jan. One can modify the assay to look for disorders, cancer, viral 2001; inhibition using any of the disclosed infections 10.1126/science.1057453 protease inhibitor polypeptides. Human monocyte GeneSeq WO9509232 Chemokines are a family of small, Chemokine activities can be determined Immune disorders, chemoattractant Accession secreted proteins involved in biological using assays known in the art: Methods in particularly useful for factor hMCP-3 R73915 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: treating bacterial and/or angiogenesis, and leukocyte trafficking. Chemokine Protocols, Edited by: A. E. I. Proudfoot, viral menigitis Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human monocyte GeneSeq WO9509232 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders, chemoattractant Accession secreted proteins involved in biological using assays known in the art: Methods in particularly useful for factor hMCP-1 R73914 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: treating bacterial and/or angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, viral menigitis Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human gro-beta GeneSeq WO9429341 Chemokines are a family of small, Chemokine activities can be determined Immune disorders, chemokine Accessions secreted proteins involved in biological using assays known in the art: Methods in inflammatory disorders, R66699 and processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: blood-related disorders, W17671 angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, stem cell transplantation, Members of this family are involved in a T. N. C. Wells, and C. A. Power. cancer similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human gro- GeneSeq WO9429341 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders, gamma Accessions secreted proteins involved in biological using assays known in the art: Methods in inflammatory disorders, chemokine R66700 and processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: blood-related disorders, W17672 angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, stem cell transplantation, Members of this family are involved in a T. N. C. Wells, and C. A. Power. cancer similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified Human gro-alpha GeneSeq WO9429341 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders, chemokine Accessions secreted proteins involved in biological using assays known in the art: Methods in inflammatory disorders, R66698 and processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: blood-related disorders, W18024 angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, stem cell transplantation, Members of this family are involved in a T. N. C. Wells, and C. A. Power. cancer similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified Human GeneSeq WO9632481 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders, eosinophil- Accession secreted proteins involved in biological using assays known in the art: Methods in particularly treatment of expressed W05186 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: eosinophilia, inflammation, chemokine (EEC) angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, allergies, asthma, Members of this family are involved in a T. N. C. Wells, and C. A. Power. leukaemia and lymphoma similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified Chemokine-like GeneSeq WO9613587 Chemokines are a family of related small, Chemokine activities can be determined Cancer and blood-related protein PF4-414 Accessions secreted proteins involved in biological using assays known in the art: Methods in disorders, particularly Full-Length and R92318 and processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: myelosuppression Mature R99809 angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified Chemokine-like GeneSeq WO9613587 Chemokines are a family of related small, Chemokine activities can be determined Cancer and blood-related protein IL-8M3 Accession secreted proteins involved in biological using assays known in the art: Methods in disorders, particularly R99812 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: myelosuppression angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ; and including inflammation, allergy, tissue Holmes et al (1991) Science 253, 1278-80. rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified Human GeneSeq WO9613587 Chemokines are a family of related small, Chemokine activities can be determined Cancer and blood-related interleukin-8 (IL-8) Accession secreted proteins involved in biological using assays known in the art: Methods in disorders, particularly R99814 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: myelosuppression angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ; and including inflammation, allergy, tissue Holmes et al (1991) Science 253, 1278-80. rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified Chemokine-like GeneSeq WO9613587 Chemokines are a family of related small, Chemokine activities can be determined Cancer and blood-related protein IL-8M1 Accessions secreted proteins involved in biological using assays known in the art: Methods in disorders, particularly Full-Length and R99815 and processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: myelosuppression Mature R99803 angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ; and including inflammation, allergy, tissue Holmes et al (1991) Science 253, 1278-80. rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified Chemokine-like GeneSeq WO9613587 Chemokines are a family of related small, Chemokine activities can be determined Cancer and blood-related protein IL-8M8 Accessions secreted proteins involved in biological using assasys known in the art: Methods disorders, particularly Full-Length and R99816 and processes ranging from hematopoiesis, in Molecular Biology, 2000, vol. 138: myelosuppression. Mature R99805 angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot; Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ; and including inflammation, allergy, tissue Holmes et al (1991) Science 253, 1278-80. rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine-like GeneSeq WO9613587 Chemokines are a family of related small, Chemokine activities can be determined Cancer and blood-related protein IL-8M8 Accessions secreted proteins involved in biological using assasys known in the art: Methods in disorders, particularly Full-Length and R99817 and processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: myelosuppression. Mature R99806 angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot; Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ; and including inflammation, allergy, tissue Holmes et al (1991) Science 253, 1278-80. rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine-like GeneSeq WO9613587 Chemokines are a family of related small, Chemokine activities can be determined Cancer and blood-related protein IL-8M8 Accessions secreted proteins involved in biological using assasys known in the art: Methods in disorders, particularly Full-Length and R99818 and processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: myelosuppression. Mature R99804 angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot; Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ; and including inflammation, allergy, tissue Holmes et al (1991) Science 253, 1278-80. rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine-like GeneSeq WO9613587 Chemokines are a family of related small, Chemokine activities can be determined Cancer and blood-related protein IL-8M8 Accessions secreted proteins involved in biological using assasys known in the art: Methods in disorders, particularly Full-Length and R99819 and processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: myelosuppression. Mature R99807 angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot; Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine-like GeneSeq WO9613587 Chemokines are a family of related small, Chemokine activities can be determined Cancer and blood-related protein IL-8M8 Accessions secreted proteins involved in biological using assasys known in the art: Methods in disorders, particularly Full-Length and R99822 and R9807 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: myelosuppression. Mature angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot; Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human foetal GeneSeq WO9622374 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders spleen expressed Accession R98499 secreted proteins involved in biological using assasys known in the art: Methods in chemokine, FSEC processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot; Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Liver expressed GeneSeq WO9616979 Chemokines are a family of related small, Chemokine activities can be determined Inflammation of the liver chemokine- Accession R95689 secreted proteins involved in biological using assasys known in the art: Methods in 1(LVEC-1) processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot; Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Liver expressed GeneSeq WO9616979 Chemokines are a family of related small, Chemokine activities can be determined Inflammation of the liver chemokine- Accession R95690 secreted proteins involved in biological using assasys known in the art: Methods in 2(LVEC-2) processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot; Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Pituitary GeneSeq WO9616979 Chemokines are a family of related small, Chemokine activities can be determined Inflammation, particularly expressed Accession R95691 secreted proteins involved in biological using assasys known in the art: Methods in of the liver chemokine processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: (PGEC) angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot; Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Adenoid- GeneSeq WO9617868 Chemokines are a family of related small, Chemokine activities can be determined Inflammation, expressed Accession R97664 secreted proteins involved in biological using assasys known in the art: Methods in angiogenesis, chemokine processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: tumorigenesis, (ADEC) angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot; musculoskeletal disorders Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9741230 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders, cell chemokineCC-2 Accession secreted proteins involved in biological using assays known in the art: Methods in migration, proliferation, W38170 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138; and differentiation angiogenesis, and leukocyte trafficking. Chemokine protocols. Edited by: A. E. I. Proudfoot, disorders Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc. Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9741230 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders, cell chemokine Accession secreted proteins involved in biological using assays known in the art: Methods in migration, proliferation, HCC-1 W38171 processes ranging from hematopiesis, molecular Biology 2000, vol. 138: and differentiation anglogenesis and leukocyte trafficking. Chemokine Protocols. Edited by A. E. I. Proudfoot, disorders Members of this family are involved in a T. N. C. Wells and C. A. Power similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9741230 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders, cell chemokine CC-3 Accession secreted proteins involved in biological using assays known in the art: Methods in migration, proliferation and W38172 processes ranging from hemotopoiesis, molecular Biology, 2000, vol. 138: differentiation disorders anglogenesis, and leukocyte trafficking. Chemokine Protocols, Edited by A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Novel GeneSeq WO9739126 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders, betachemokine Accession secreted proteins involved in biological using assays known in the art: Methods in vascular disorders, cancer designated PTEC W27271 processes ranging from hemotopoiesis, molecular Biology, 2000, vol. 138: anglogenesis, and leukocyte trafficking. Chemokine Protocols, Edited by A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human CX3C GeneSeq WO9727299 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders, 111 amino acid Accession secreted proteins involved in biological using assays known in the art: Methods in inflammatory diseases, chemokine W23344 processes ranging from hemotopoiesis, molecular Biology, 2000, vol. 138: abnormal proliferation, anglogenesis, and leukocyte trafficking. Chemokine Protocols, Edited by A. E. I. Proudfoot, regeneration, Members of this family are involved in a T. N. C. Wells, and C. A. Power degeneration, and atrophy similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human CCF18 GeneSeq WO9721812 Chemokines are a family of related small, Chemokine activities can be determined Abnormal physiology and chemokine Accession secreted proteins involved in biological using assays known in the art: Methods in development disorders, W25942 processes ranging from hemotopoiesis, molecular Biology, 2000, vol. 138: can also be used as an anglogenesis, and leukocyte trafficking. Chemokine Protocols, Edited by A. E. I. Proudfoot, anti-viral agent Members of this family are involved in a T. N. C. Wells, and C. A. Power similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human beta- GeneSeq WO9725427 Chemokines are a family of related small, Chemokine activities can be determined Chemotaxis, blood-related chemokine Accession secreted proteins involved in biological using assays known in the art: Methods in disorders, viral infection, H1305 (MCP-2) W26655 processes ranging from hemotopoiesis, molecular Biology, 2000, vol. 138: HIV, wound healing, anglogenesis, and leukocyte trafficking. Chemokine Protocols, Edited by A. E. I. Proudfoot, cancer Members of this family are involved in a T. N. C. Wells, and C. A. Power similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9712914 Chemokines are a family of related small, Chemokine activities can be determined Inflammatory and immune eosinocyte CC Accession secreted proteins involved in biological using assays known in the art: Methods in disorders type chemokine W14990 processes ranging from hemotopoiesis, molecular Biology, 2000, vol. 138: eotaxin anglogenesis, and leukocyte trafficking. Chemokine Protocols, Edited by A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human thymus GeneSeq WO9711969 Chemokines are a family of related small, Chemokine activities can be determined Inflammatory and immune and activation Accession secreted proteins involved in biological using assays known in the art: Methods in disorders regulated W14018 processes ranging from hemotopoiesis, molecular Biology, 2000, vol. 138: cytokine anglogenesis, and leukocyte trafficking. Chemokine Protocols, Edited by A. E. I. Proudfoot, (TARC) Members of this family are involved in a T. N. C. Wells, and C. A. Power similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9712041 Chemokines are a family of related small, Chemokine activities can be determined Cancer, would healing, chemokine beta- Accession secreted proteins involved in biological using assays known in the art: Methods in immune disorders 8 short forms W16315 processes ranging from hemotopoiesis, molecular Biology, 2000, vol. 138: anglogenesis, and leukocyte trafficking. Chemokine Protocols, Edited by A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Microphage GeneSeq WO9640923 Chemokines are a family of related small, Chemokine activities can be determined Inflammatory diseases, derived Accession secreted proteins involved in biological using assays known in the art: Methods in wound healin, chemokine, MDC W20058 processes ranging from hermaatopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9844117 Chemokines are a family of related small, Chemokine activities can be determined Inflammatory and immune chemokine ZSIG- Accession secreted proteins involved in biological using assays known in the art: Methods in diseases 35 W30565 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Primate CC GeneSeq WO98328658 Chemokines are a family of related small, Chemokine activities can be determined Immune and inflammatory chemokine Accesssion secreted proteins involved in biological using assays known in the art: Methods in disorders, abnormal “ILINCK” W69990 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: proliferation, regeneration, angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Prodfoot, generation and atrophy T. N. C. Wells, and C. A. Power. disorders © Humana Press Inc., Totowa, NJ Primate CXC GeneSeq WO9832858 Chemokines are a family of related small, Chemokine activities can be determined Immune and inflammatory chemokine Accession secreted proteins involved in biological using assays known in the art: Methods in disorders, abnormal “IBICK” W69989 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: proliferation, regeneration, angiogenesis, and leukocyte trafficking. Chemokine Protocols. Editd by: A. E. I. Proudfoot, generation and atrophy Members of this family are involved in a T. N. C. Wells, and C. A. Power. disorders similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human CC-type GeneSeq WO9831809 Chemokines are a family of related small, Chemokine activities can be determined Immune, inflammatory, chemokine protein Accession secreted proteins involved in biological using assays known in the art: Methods in and infectious disorders, designated SLC W69163 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: cancer (secondary angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, lymphoid Members of this family are involved in a T. N. C. Wells, and C. A. Power. chemokine) similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human CC GeneSeq WO9826071 Chemokines are a family of related small, Chemokine activities can be determined Cancer and infectious chemokine ELC Accession secreted proteins involved in biological using assays known in the art: Methods in diseases, particularly protein W62542 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: herpes virus angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human DVic-1 GeneSeq Wo9823750 Chemokines are a family of related small, Chemokine activities can be determined Abnormal proliferation, C-C chemokine Accession secreted proteins involved in biological using assays known in the art: Methods in regeneration, W60649 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: degeneration, and atrophy angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, disorders, including cancer Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human C-C GeneSeq WO9823750 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders, cell chemokine Accession secreted proteins involved in biological using assays known in the art: Methods in proliferation disorders, DGWCC W60650 processes ranging from hematophoiesis, Molecular Biology, 2000, vol. 138: cancer angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identifed. Human STCP-1 GeneSeq WO9824907 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders, Accession secreted proteins involved in biological using assays known in the art: Methods in particularly T cell related W62783 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: disorders, viral infection, angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, and inflammation, Members of this family are involved in a T. N. C. Wells, and C. A. Power. especially joint similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Exodua protein GeneSeq WO9821330 Chamokines are a family of related small, Chemokine activities can be determined Immune and inflammatory Accession secreted proteins involved in biological using assays known in the art: Methods in disorders, angiogenesis, W61279 processes ranging from hematopoiesis, Molecular Biology, 2000, vol.138: cancer, and proliferation angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, disorders, particularly Members of this family are involved in a T. N. C. Wells, and C. A. Power. myeloproliferative similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ diseases including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9814581 Chemokines are a family of related small, Chemokine activities can be determined Cancer and degenerative Chr19Kine Acession secreted proteins involved in biological using assays known in the art: Methods in disorders protein W50887 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine Protocols, Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human T cell GeneSeq U.S. Pat. No. 5,780,268 Chemokines are a family of related Chemokine activities can be determined Immune, inflammatory, mixed Accession small, secreted proteins involved in using assays known in the art: Mehtods of and infectious disorders, lymphocyte W58703 biological processes ranging from Molecular Biology, 2000, vol. 138: cancer reaction hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. I. Proudfoot, expressed leukocyte trafficking. Members of this T. N. C. Wells, and C. A. Power chemokine family are involved in a similarly diverse © Humana Press Inc., Totowa, NJ (TMEC) range of pathologies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human 6CKine GeneSeq W09814581 Chemokines are a family of related Chemokine activities can be determined Cancer and degenerative protein Accession small, secreted proteins involved in using assays known in the art: Mehtods of disorders W50885 biological processes ranging from Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. I. Proudfoot, leukocyte trafficking. Members of this T. N. C. Wells, and C. A. Power family are involved in a similarly diverse © Humana Press Inc., Totowa, NJ range of pathologies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. human liver and GeneSeq WO9817800 Chemokines are a family of related Chemokine activities can be determined Immune, inflammatory, activation Accession small, secreted proteins involved in using assays known in the art: Mehtods of and infectious disorders, regulated W57475 biological processes ranging from Molecular Biology, 2000, vol. 138: cancer chemokine hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. I. Proudfoot, (LARC) leukocyte trafficking. Members of this T. N. C. Wells, and C. A. Power family are involved in a similarly diverse © Humana Press Inc., Totowa, NJ range of pathologies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. RANTES GeneSeq WO9744462 Chemokines are a family of related Chemokine activities can be determined Infectious diseases, peptide Accession small, secreted proteins involved in using assays known in the art: Mehtods of particularly HIV W29538 biological processes ranging from Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. I. Proudfoot, leukocyte trafficking. Members of this T. N. C. Wells, and C. A. Power family are involved in a similarly diverse © Humana Press Inc., Totowa, NJ range of pathologies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. RANTES 8-68 GeneSeq WO9744462 Chemokines are a family of related Chemokine activities can be determined Infectious diseases, Accession small, secreted proteins involved in using assays known in the art: Mehtods of particularly HIV W29529 biological processes ranging from Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. I. Proudfoot, leukocyte trafficking. Members of this T. N. C. Wells, and C. A. Power family are involved in a similarly diverse © Humana Press Inc., Totowa, NJ range of pathologies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. RANTES 9-68 GeneSeq WO9744462 Chemokines are a family of related Chemokine activities can be determined Infectious diseases, Accession small, secreted proteins involved in using assays known in the art: Mehtods of particularly HIV W29528 biological processes ranging from Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. I. Proudfoot, leukocyte trafficking. Members of this T. N. C. Wells, and C. A. Power family are involved in a similarly diverse © Humana Press Inc., Totowa, NJ range of pathologies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9811226 Chemokines are a family of related Chemokine activities can be determined Abnormal proliferation, chemokine Accession small, secreted proteins involved in using assays known in the art: Mehtods of regeneration, protein 331D5 W59433 biological processes ranging from Molecular Biology, 2000, vol. 138: degeneration or atrophy, hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. I. Proudfoot, including cancer leukocyte trafficking. Members of this T. N. C. Wells, and C. A. Power family are involved in a similarly diverse © Humana Press Inc., Totowa, NJ range of pathologies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9811226 Chemokines are a family of related Chemokine activities can be determined Abnormal proliferation, chemokine Accession small, secreted proteins involved in using assays known in the art: Mehtods of regeneration, protein 61164 W59430 biological processes ranging from Molecular Biology, 2000, vol. 138: degeneration or atrophy, hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. I. Proudfoot, including cancer leukocyte trafficking. Members of this T. N. C. Wells, and C. A. Power family are involved in a similarly diverse © Humana Press Inc., Totowa, NJ range of pathologies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine GeneSeq WO9809171 Chemokines are a family of related Chemokine activities can be determined Immune, Inflammatory, MCP-4 Accession small, secreted proteins involved in using assays known in the art: Mehtods of and infectious diseases W56690 biological processes ranging from Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. I. Proudfoot, leukocyte trafficking. Members of this T. N. C. Wells, and C. A. Power family are involved in a similarly diverse © Humana Press Inc., Totowa, NJ range of pathologies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human stromal GeneSeq FR2751658 Chemokines are a family of related small, Chemokine activities can be determined HIV infections cell-derived Accession secreted proteins involved in biological using assays known in the art: Methods in chemokine, SDF-1 W50766 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Thymus GeneSeq WO9801557 Chemokines are a family of related small, Chemokine activities can be determined Immune and inflammatory expressed Accession W44397 secreted proteins involved in biological using assays known in the art: Methods in disorders chemokine processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: (TECK) angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9801557 Chemokines are a family of related small, Chemokine activities can be determined Immune and inflammatory chemokine MIP- Accession W44398 secreted proteins involved in biological using assays known in the art: Methods in disorders 3alpha processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9801557 Chemokines are a family of related small, Chemokine activities can be determined Immune and inflammatory chemokine MIP- Accession W44399 secreted proteins involved in biological using assays known in the art: Methods in disorders 3beta processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human monocyte GeneSeq WO9802459 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders, chemotactic Accession W42072 secreted proteins involved in biological using assays known in the art: Methods in respiratory disorders, proprotein processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: cancer (MCPP) sequence angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Macrophage- GeneSeq U.S. Pat. No. 5,688,927/ Chemokines are a family of related small, Chemokine activities can be determined Immune, and inflammatory derived Accessions U.S. Pat. No. 5,932,703 secreted proteins involved in biological using assays known in the art: Methods in disorders, cancer chemokine (MDC) W40811 and processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: Y24414 angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Macrophage GeneSeq U.S. Pat. No. 5,932,703 Chemokines are a family of related small, Chemokine activities can be determined Immune and inflammatory derived Accession Y24416 secreted proteins involved in biological using assays known in the art: Methods in disorders chemokine processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: analogue MDC- angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, eyfy Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Macrophage GeneSeq U.S. Pat. No. 5,932,703 Chemokines are a family of related small, Chemokine activities can be determined Immune and inflammatory derived Accession Y24413 secreted proteins involved in biological using assays known in the art: Methods in disorders chemokine processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: analogue MDC angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, (n + 1) Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Macrophage GeneSeq U.S. Pat. No. 5,932,703 Chemokines are a family of related small, Chemokine activities can be determined Immune and inflammatory derived Accession Y24415 secreted proteins involved in biological using assays known in the art: Methods in disorders chemokine processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: analogue MDC-yl angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human type CC GeneSeq JP11243960 Chemokines are a family of related small, Chemokine activities can be determined Allergic diseases and HIV chemokine Accession Y43178 secreted proteins involved in biological using assays known in the art: Methods in infection eotaxin 3 protein processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: sequence angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human MCP-3 GeneSeq WO9946392 Chemokines are a family of related small, Chemokine activities can be determined Cancer and immune and human Muc-1 Acession Y29893 secreted proteins involved in biological using assays known in the art: Methods in disorders, particularly HIV core epitope processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: infection (VNT) fusion angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, protein Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarily diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human IP-10 and GeneSeq WO9946392 Chemokines are a family of related small, Chemokine activities can be determined Cancer and immune human Muc-1 Accession Y29894 secreted proteins involved in biological using assays known in the art: Methods in disorders, particularly HIV core epitope processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: infection (VNT) fusion angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, protein Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarily diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human IP-10 and GeneSeq W09946392 Chemokines are a family of related small, Chemokine activities can be determined Cancer and immune HIV-1 gp 120 Accession Y29897 secreted proteins involved in biological using assays known in the art: Methods in disorders, particularly HIV hypervariable processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: infection region fusion angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, protein Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarily diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human mammary GeneSeq WO9936540 Chemokines are a family of related small, Chemokine activities can be determined Breast disease, including associated Accessions secreted proteins involved in biological using assays known in the art: Methods in cancer chemokine Y29092 and processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: (MACK) protein Y29093 angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Full-Length and Members of this family are involved in a T. N. C. Wells, and C. A. Power. Mature similarily diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Tim-1 protein GeneSeq WO9933990 Chemokines are a family of related small, Chemokine activities can be determined Inflammation due to stimuli Accession secreted proteins involved in biological using assays known in the art: Methods in such as heart attacks and Y28290 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: stroke, infection, physical angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, trauma, UV or ionizing Members of this family are involved in a T. N. C. Wells, and C. A. Power. radiation, burns, frostbite similarily diverse range of pathologies © Humana Press Inc., Totowa, NJ or corrosive chemicals including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human Lkn-1 Full- GeneSeq WO9928473 Chemokines are a family of related small, Chemokine activities can be determined HIV infection and cancer, Length and Accessions and secreted proteins involved in biological using assays known in the art: Methods in particularly leukemia Mature protein Y17280, Y17274, WO9928472 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: Y17281, and angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Y17275 Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarily diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. N-terminal GeneSeq WO9920759 Chemokines are a family of related small, Chemokine activities can be determined Inhibit or stimulate modified Accession Y05818 secreted proteins involved in biological using assays known in the art: Methods in angiogenesis, inhibit the chemokine met- processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: binding of HIV hSDF-1 alpha angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarily diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. N-terminal GeneSeq WO9920759 Chemokines are a family of related small, Chemokine activities can be determined Inhibit or stimulate modified Accession Y05819 secreted proteins involved in biological using assays known in the art: Methods in angiogenesis, inhibit the chemokine met- processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: binding of HIV, hSDF-1 beta angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, antiinflammatory; Members of this family are involved in a T. N. C. Wells, and C. A. Power. immunosuppressant similarily diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. N-terminal GeneSeq WO9920759 Chemokines are a family of related small, Chemokine activities can be determined Inhibit or stimulate modified Accession Y05820 secreted proteins involved in biological using assays known in the art: Methods in angiogenesis, inhibit the chemokine processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: binding of HIV, GroHEK/hSDF- angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, antiinflammatory; 1alpha Members of this family are involved in a T. N. C. Wells, and C. A. Power. immunosuppressant similarily diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. N-terminal GeneSeq WO9920759 Chemokines are a family of related small, Chemokine activities can be determined Inhibit or stimulate modified Accession Y05821 secreted proteins involved in biological using assays known in the art: Methods in angiogenesis, inhibit the chemokine processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: binding of HIV, GroHEK/hSDF- angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, antiinflammatory; 1beta. Members of this family are involved in a T. N. C. Wells, and C. A. Power. immunosuppressant similarily diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine GeneSeq WO9912968 Chemokines are a family of related small, Chemokine activities can be determined Increase or enhance an Eotaxin Accession secreted proteins involved in biological using assays known in the art: Methods in inflammatory response, an Y14230 processes ranging from hematopoiesis, Molecular Bilogy, 2000, vol. 138: immune response agiogenesis, and leukocye trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, orhaematopoietic cell- Members of this family are involved in a T. N. C. Wells, and C. A. Power. associated activity; treat a similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ vascular indication; including inflammation, allergy, tissue Cancer; enhance wound rejection, viralk infection, and tumor healing, to prevent or treat biology. The chemokines exert their asthma, organ transplant effects by acting on a family of seven rejction, rheumatoid transmembrane G-protein-coupled arthritis or allergy receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine GeneSeq WO9912968 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders, hMCP1a Accession secreted proteins involved in biological using assays known in the art: Methods in Vascular disorders, Y14225 processes ranging from hematopoiesis, Molecular Bilogy, 2000, vol. 138: Wound healing, cancer, agiogenesis, and leukocye trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, prevent organ transplant Members of this family are involved in a T. N. C. Wells, and C. A. Power. rejection, Increase or similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ enhance an inflammatory including inflammation, allergy, tissue response, rejection, viralk infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine GeneSeq WO9912968 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders, hMCP1b Accession secreted proteins involved in biological using assays known in the art: Methods in Vascular disorders, Y14226 processes ranging from hematopoiesis, Molecular Bilogy, 2000, vol. 138: Wound healing, cancer, agiogenesis, and leukocye trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, prevent organ transplant Members of this family are involved in a T. N. C. Wells, and C. A. Power. rejection, Increase or similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ enhance an inflammatory including inflammation, allergy, tissue response, rejection, viralk infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine GeneSeq WO9912968 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders, hSDF1b Accession secreted proteins involved in biological using assays known in the art: Methods in Vascular disorders, Y14228 processes ranging from hematopoiesis, Molecular Bilogy, 2000, vol. 138: Wound healing, cancer, agiogenesis, and leukocye trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, prevent organ transplant Members of this family are involved in a T. N. C. Wells, and C. A. Power. rejection, Increase or similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ enhance an inflammatory including inflammation, allergy, tissue response, rejection, viralk infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine GeneSeq WO9912968 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders, hIL-8 Accession secreted proteins involved in biological using assays known in the art: Methods in Vascular disorders, Y14229 processes ranging from hematopoiesis, Molecular Bilogy, 2000, vol. 138: Wound healing, cancer, agiogenesis, and leukocye trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, prevent organ transplant Members of this family are involved in a T. N. C. Wells, and C. A. Power. rejection, Increase or similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ; and enhance an inflammatory including inflammation, allergy, tissue Holmes et al (1991) Science 253, 1278-80. response, rejection, viralk infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine GeneSeq WO9912968 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders, hMCP1 Accession secreted proteins involved in biological using assays known in the art: Methods in Vascular disorders, Y14222 processes ranging from hematopoiesis, Molecular Bilogy, 2000, vol. 138: Wound healing, cancer, agiogenesis, and leukocye trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, prevent organ transplant Members of this family are involved in a T. N. C. Wells, and C. A. Power. rejection, Increase or similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ enhance an inflammatory including inflammation, allergy, tissue response, rejection, viralk infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine GeneSeq WO9912968 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders, hMCP2 Accession secreted proteins involved in biological using assays known in the art: Methods in Vascular disorders, Y14223 processes ranging from hematopoiesis, Molecular Bilogy, 2000, vol. 138: Wound healing, cancer, agiogenesis, and leukocye trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, prevent organ transplant Members of this family are involved in a T. N. C. Wells, and C. A. Power. rejection, Increase or similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ enhance an inflammatory including inflammation, allergy, tissue response, rejection, viralk infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine GeneSeq WO9912968 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders, hMCP3 Accession secreted proteins involved in biological using assays known in the art: Methods in Vascular disorders, Y14224 processes ranging from hematopoiesis, Molecular Bilogy, 2000, vol. 138: Wound healing, cancer, agiogenesis, and leukocye trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, prevent organ transplant Members of this family are involved in a T. N. C. Wells, and C. A. Power. rejection, Increase or similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ enhance an inflammatory including inflammation, allergy, tissue response, rejection, viralk infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. C-C chemokine, GeneSeq EP905240 Chemokines are a family of related small, Chemokine activities can be determined Inflammatory, Immune and MCP2 Accession secreted proteins involved in biological using assays known in the art: Methods in infectious diseases; Y05300 processes ranging from hematopoiesis, Molecular Bilogy, 2000, vol. 138: pulmonary diseases and agiogenesis, and leukocye trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, skin disorders; tumours, Members of this family are involved in a T. N. C. Wells, and C. A. Power. and angiogenesis-and similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ haematopoiesis-related including inflammation, allergy, tissue diseases rejection, viralk infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Wild type GeneSeq EP906954 Chemokines are a family of related small, Chemokine activities can be determined Inflammatory, Immune and monocyte Accession secreted proteins involved in biological using assays known in the art: Methods in infectious diseases; chemotactic Y07233 processes ranging from hematopoiesis, Molecular Bilogy, 2000, vol. 138: pulmonary diseases and protein 2 agiogenesis, and leukocye trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, skin disorders; tumours, Members of this family are involved in a T. N. C. Wells, and C. A. Power. and angiogenesis-and similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ haematopoiesis-related including inflammation, allergy, tissue diseases rejection, viralk infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Truncated GeneSeq EP906954 Chemokines are a family of related small, Chemokines activities can be determined Inflammatory, immune and monocyte Accession secreted proteins involved in biological using assays known in the art: Methods in infectious diseases; chemotactic Y07234 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: pulmonry diseases and skin protein 2 (6-76) angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, disorders; tumours, and Members of this family are involved in a T. N. C. Wells, and C. A. Power, angiogenesis-and similarly diverse range of pathologies Humana Press Inc., Totowa, NJ haematopoiesis-related including inflammation, allergy, tissue diseases rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a fmaily of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Truncated GeneSeq EP905241; Chemokines are a family of related small, Chemokines activities can be determined Inflammatory, immune and RANTES Accessions EP906954 secreted proteins involved in biological using assays known in the art: Methods in infectious diseases; protein (3-68) Y07236 and processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: pulmonry diseases and skin Y07232 angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, disorders; tumours, and Members of this family are involved in a T. N. C. Wells, and C. A. Power, angiogenesis-and similarly diverse range of pathologies Humana Press Inc., Totowa, NJ haematopoiesis-related including inflammation, allergy, tissue diseases rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a fmaily of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Wild type GeneSeq EP905241 Chemokines are a family of related small, Chemokines activities can be determined Inflammatory, immune and monocyte Accession secreted proteins involved in biological using assays known in the art: Methods in infectious diseases; chemotactic Y07237 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: pulmonry diseases and skin protein 2 angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, disorders; tumours, and Members of this family are involved in a T. N. C. Wells, and C. A. Power, angiogenesis-and similarly diverse range of pathologies Humana Press Inc., Totowa, NJ haematopoiesis-related including inflammation, allergy, tissue diseases rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a fmaily of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Truncated GeneSeq EP905241 Chemokines are a family of related small, Chemokines activities can be determined Inflammatory, immune and monocyte Accession secreted proteins involved in biological using assays known in the art: Methods in infectious diseases; chemotactic Y07238 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: pulmonry diseases and skin protein 2 (6-76) angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, disorders; tumours, and Members of this family are involved in a T. N. C. Wells, and C. A. Power, angiogenesis-and similarly diverse range of pathologies Humana Press Inc., Totowa, NJ haematopoiesis-related including inflammation, allergy, tissue diseases rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a fmaily of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. A partial GeneSeq EP897980 Chemokines are a family of related small, Chemokines activities can be determined Soluble CXCR4B receptor CXCR4B Accession secreted proteins involved in biological using assays known in the art: Methods in polypeptides may be useful protein W97363 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: for inhibiting chemokine angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, activities and viral infection. Members of this family are involved in a T. N. C. Wells, and C. A. Power, similarly diverse range of pathologies Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a fmaily of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Interferon GeneSeq U.S. Pat. No. 5,871,723 Chemokines are a family of related small, Chemokines activities can be determined Angiogenesis, Cancer, gamma- Accession secreted proteins involved in biological using assays known in the art: Methods in Inflammatory and Immune inducible W96709 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: disorders, Cardio-Vascular protein (IP-10) angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, discorders, Musco-skeletal Members of this family are involved in a T. N. C. Wells, and C. A. Power, disorders similarly diverse range of pathologies Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a fmaily of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. A monokine GeneSeq U.S. Pat. No. 5,871,723 Chemokines are a family of related small, Chemokines activities can be determined Angiogenesis, Cancer, induced by Accession secreted proteins involved in biological using assays known in the art: Methods in Inflammatory and Immune gamma- W96710 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: disorders, Cardio-Vascular interferon angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, discorders, Musco-skeletal (MIG) Members of this family are involved in a T. N. C. Wells, and C. A. Power, disorders similarly diverse range of pathologies Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a fmaily of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Interleukin-8 GeneSeq U.S. Pat. No. 5,871,723 Chemokines are a family of related small, Chemokines activities can be determined Angiogenesis, Cancer, (IL-8) protein. Accession secreted proteins involved in biological using assays known in the art: Methods in Inflammatory and Immune W96711 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: disorders, Cardio-Vascular angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, discorders, Musco-skeletal Members of this family are involved in a T. N. C. Wells, and C. A. Power, disorders similarly diverse range of pathologies Humana Press Inc., Totowa, NJ; and including inflammation, allergy, tissue Holmes et al (1991) Science 253, 1278-80. rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a fmaily of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Epithelial GeneSeq U.S. Pat. No. 5,871,723 Chemokines are a family of related small, Chemokines activities can be determined Angiogenesis, Cancer, neutrophil Accession secreted proteins involved in biological using assays known in the art: Methods in Inflammatory and Immune activating W96712 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: disorders, Cardio-Vascular protein-78 angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, discorders, Musco-skeletal (ENA-78) Members of this family are involved in a T. N. C. Wells, and C. A. Power, disorders similarly diverse range of pathologies Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a fmaily of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Growth related GeneSeq U.S. Pat. No. 5,871,723 Chemokines are a family of related small, Chemokines activities can be determined Angiogenesis, Cancer, oncogene-alpha Accession secreted proteins involved in biological using assays known in the art: Methods in Inflammatory and Immune (GRO-alpha). W96713 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: disorders, Cardio-Vascular angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, discorders, Musco-skeletal Members of this family are involved in a T. N. C. Wells, and C. A. Power, disorders similarly diverse range of pathologies Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a fmaily of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Growth related GeneSeq U.S. Pat. No. 5,871,723 Chemokines are a family of related small, Chemokine activities can be determined Angiogenesis, Cancer, oncogene-beta Accession secreted proteins involved in biological using assays known in the art: Methods in Inflammatory and Immune (GRO-beta). W96714 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: disorders, Cardio-Vascular angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, disorders, Musco-skeletal Members of this family are involved in a T. N. C. Wells, and C. A. Power, disorders similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified Growth related GeneSeq U.S. Pat. No. 5,871,723 Chemokines are a family of related small, Chemokine activities can be determined Angiogenesis, Cancer, oncogene-gamma Accession W96715 secreted proteins involved in biological using assays known in the art: Methods in Inflammatory and Immune (GRO-gamma) processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: disorders, Cardio-Vascular angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, disorders, Musco-skeletal Members of this family are involved in a T. N. C. Wells, and C. A. Power, disorders similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. A platelet basic GeneSeq U.S. Pat. No. 5,871,723 Chemokines are a family of related small, Chemokine activities can be determined Angiogenesis, Cancer, protein (PBP) Accession W96716 secreted proteins involved in biological using assays known in the art: Methods in Inflammatory and Immune processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: disorders, Cardio-Vascular angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, disorders, Musco-skeletal Members of this family are involved in a T. N. C. Wells, and C. A. Power, disorders similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Connective tissue GeneSeqAccession U.S. Pat. No. 5,871,723 Chemokines are a family of related small, Chemokine activities can be determined Angiogenesis, Cancer, activating protein- S96717 secreted proteins involved in biological using assays known in the art: Methods in Inflammatory and Immune III (CTAP-III) processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: disorders, Cardio-Vascular angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, disorders, Musco-skeletal Members of this family are involved in a T. N. C. Wells, and C. A. Power, disorders similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Beta- GeneSeq U.S. Pat. No. 5,871,723 Chemokines are a family of related small, Chemokine activities can be determined Angiogenesis, Cancer, thromboglobulin Accession W96718 secreted proteins involved in biological using assays known in the art: Methods in Inflammatory and Immune protein (beta-TG) processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: disorders, Cardio-Vascular angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, disorders, Musco-skeletal Members of this family are involved in a T. N. C. Wells, and C. A. Power, disorders similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Neutrophil GeneSeq U.S. Pat. No. 5,871,723 Chemokines are a family of related small, Chemokine activities can be determined Angiogenesis, Cancer, activating peptide- Accession W96719 secreted proteins involved in biological using assays known in the art: Methods in Inflammatory and Immune 2 (NAP-2) processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: disorders, Cardio-Vascular angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, disorders, Musco-skeletal Members of this family are involved in a T. N. C. Wells, and C. A. Power, disorders similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Granulocyte GeneSeq U.S. Pat. No. 5,871,723 Chemokines are a family of related small, Chemokine activities can be determined Angiogenesis, Cancer, chemotactic Accession W96720 secreted proteins involved in biological using assays known in the art: Methods in Inflammatory and Immune protein-2 (GCP-2) processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: disorders, Cardio-Vascular angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, disorders, Musco-skeletal Members of this family are involved in a T. N. C. Wells, and C. A. Power, disorders similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq EP887409 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders, viral, chemokine MIG- Accession W90124 secreted proteins involved in biological using assays known in the art: Methods in parasitic, fungal or beta protein processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: bacterial infections, angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Cancer; autoimmune Members of this family are involved in a T. N. C. Wells, and C. A. Power, diseases or transplant similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ rejection including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human ZCHEMO-8 GeneSeq WO9854326 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders, cancer, Accession W82716 secreted proteins involved in biological using assays known in the art: Methods in myelopoietic disorders, processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: autoimmune disorders and angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, immunodeficiencies, Members of this family are involved in a T. N. C. Wells, and C. A. Power, Inflammatory and similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ infectious diseases, including inflammation, allergy, tissue Vascular disorders, wound rejection, viral infection, and tumor healing biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human Act-2 GeneSeq WO9854326 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders, cancer, protein Accession W82717 secreted proteins involved in biological using assays known in the art: Methods in myelopoietic disorders, processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: autoimmune disorders and angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, immunodeficiencies, Members of this family are involved in a T. N. C. Wells, and C. A. Power, Inflammatory and similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ infectious diseases, including inflammation, allergy, tissue Vascular disorders, wound rejection, viral infection, and tumor healing biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human SISD GeneSeq WO9854326 Chemokines are a family of related small, Chemokine activities can be determined Immune disorders, cancer, protein Acession secreted proteins involved in biological using assays known in the art: Methods in myelopoietic disorders, W82720 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: autoimmune disorders and angiogenesis, and leukocyte trafficking. Chemokine Protocols, Edited by: A. E. I. Proudfoot, immunodeficiencies, Members of this family are involved in a T. N. C. Wells, and C. A. Power. Inflammatory and similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ infectious diseases, including inflammation, allergy, tissue Vascular disorders, wound rejection, viral infection, and tumor healing biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human M110 GeneSeq WO9854326 Chemokines are a family of related Chemokine activities can be determined Immune disorders, cancer, protein Accession small, secreted proteins involved in using assays known in the art: Mehtods of myelopoietic disorders, W82721 biological processes ranging from Molecular Biology, 2000, vol. 138: autoimmune disorders and hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. I. Proudfoot, immunodeficiencies, leukocyte trafficking. Members of this T. N. C. Wells, and C. A. Power Inflammatory and family are involved in a similarly diverse © Humana Press Inc., Totowa, NJ infectious diseases, range of pathologies including Vascular disorders, wound inflammation, allergy, tissue rejection, healing viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human M11A GeneSeq W09854326 Chemokines are a family of related Chemokine activities can be determined Immune disorders, cancer, protein Accession small, secreted proteins involved in using assays known in the art: Mehtods of myelopoietic disorders, W82722 biological processes ranging from Molecular Biology, 2000, vol. 138: autoimmune disorders and hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. I. Proudfoot, immunodeficiencies, leukocyte trafficking. Members of this T. N. C. Wells, and C. A. Power Inflammatory and family are involved in a similarly diverse © Humana Press Inc., Totowa, NJ infectious diseases, range of pathologies including Vascular disorders, wound inflammation, allergy, tissue rejection, healing viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human CCC3 GeneSeq WO9854326 Chemokines are a family of related Chemokine activities can be determined Immune disorders, cancer, protein Accession small, secreted proteins involved in using assays known in the art: Mehtods of myelopoietic disorders, W82723 biological processes ranging from Molecular Biology, 2000, vol. 138: autoimmune disorders and hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. I. Proudfoot, immunodeficiencies, leukocyte trafficking. Members of this T. N. C. Wells, and C. A. Power Inflammatory and family are involved in a similarly diverse © Humana Press Inc., Totowa, NJ infectious diseases, range of pathologies including Vascular disorders, wound inflammation, allergy, tissue rejection, healing viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. A human L105 GeneSeq WO9856818 Chemokines are a family of related Chemokine activities can be determined Cancer, wound healing chemokine Accession small, secreted proteins involved in using assays known in the art: Mehtods of designated W87588 biological processes ranging from Molecular Biology, 2000, vol. 138: huL105_3. hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. I. Proudfoot, leukocyte trafficking. Members of this T. N. C. Wells, and C. A. Power family are involved in a similarly diverse © Humana Press Inc., Totowa, NJ range of pathologies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. A human L105 GeneSeq WO9856818 Chemokines are a family of related Chemokine activities can be determined Cancer, wound healing chemokine Accession small, secreted proteins involved in using assays known in the art: Mehtods of designated W87589 biological processes ranging from Molecular Biology, 2000, vol. 138: huL105_7. hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. I. Proudfoot, leukocyte trafficking. Members of this T. N. C. Wells, and C. A. Power family are involved in a similarly diverse © Humana Press Inc., Totowa, NJ range of pathologies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human mature GeneSeq WO9848828 Chemokines are a family of related Chemokine activities can be determined Infectious diseases, sepsis gro-alpha Accession small, secreted proteins involved in using assays known in the art: Mehtods of polypeptide W81498 biological processes ranging from Molecular Biology, 2000, vol. 138: used to treat hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. I. Proudfoot, sepsis leukocyte trafficking. Members of this T. N. C. Wells, and C. A. Power family are involved in a similarly diverse © Humana Press Inc., Totowa, NJ range of pathologies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human mature GeneSeq WO9848828 Chemokines are a family of related Chemokine activities can be determined Infectious diseases, sepsis gro-gamma Accession small, secreted proteins involved in using assays known in the art: Mehtods of polypeptide W81500 biological processes ranging from Molecular Biology, 2000, vol. 138: used to treat hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. I. Proudfoot, sepsis leukocyte trafficking. Members of this T. N. C. Wells, and C. A. Power family are involved in a similarly diverse © Humana Press Inc., Totowa, NJ range of pathologies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human thymus GeneSeq WO0053635 Chemokines are a family of related Chemokine activities can be determined Inflammatory disorders, expressed Accessions small, secreted proteins involved in using assays known in the art: Mehtods of cancer, Immune and chemokine B19607 and biological processes ranging from Molecular Biology, 2000, vol. 138: vascular disorders TECK and B19608 hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. I. Proudfoot, TECK variant leukocyte trafficking. Members of this T. N. C. Wells, and C. A. Power family are involved in a similarly diverse © Humana Press Inc., Totowa, NJ range of pathologies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related Chemokine activities can be determined Autoimmune disorders, chemokine Accession B15791 small, secreted proteins involved in using assays known in the art: Mehtods of Immune, Vascular and SDF1alpha biological processes ranging from Molecular Biology, 2000, vol. 138: Inflammatory disorders hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. I. Proudfoot, leukocyte trafficking. Members of this T. N. C. Wells, and C. A. Power family are involved in a similarly diverse © Humana Press Inc., Totowa, NJ range of pathologies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related small, Chemokine activities can be determined Autoimmune disorders, chemokine Accession B15793 secreted proteins involved in biological using assasys known in the art: Methods Immune, Vascular and GROalpha processes ranging from hematopoiesis, in Molecular Biology, 2000, vol. 138: Inflammatory diorders angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot; Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related small, Chemokine activities can be determined Autoimmune disorders, chemokine Accession B15794 secreted proteins involved in biological using assasys known in the art: Methods in Immune, Vascular and eotaxin processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: Inflammatory disorders angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot; Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related small, Chemokine activities can be determined Autoimmune disorders, chemokine MIG Accession B15803 secreted proteins involved in biological using assasys known in the art: Methods in Immune, Vascular and processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: Inflammatory disorders angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot; Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related small, Chemokine activities can be determined Autoimmune disorders, chemokine PF4 Accession B15804 secreted proteins involved in biological using assasys known in the art: Methods in Immune, Vascular and processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: Inflammatory disorders angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot; Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related small, Chemokine activities can be determined Autoimmune disorders, chemokine I-309 Accession B15805 secreted proteins involved in biological using assasys known in the art: Methods in Immune, Vascular and processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: Inflammatory disorders angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot; Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related small, Chemokine activities can be determined Autoimmune disorders, chemokine HCC-1 Accession B15806 secreted proteins involved in biological using assasys known in the art: Methods in Immune, Vascular and processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: Inflammatory disorders angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot; Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related small, Chemokine activities can be determined Autoimmune disorders, chemokine C10 Accession B15807 secreted proteins involved in biological using assasys known in the art: Methods in Immune, Vascular and processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: Inflammatory disorders angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot; Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related small, Chemokine activities can be determined Autoimmune disorders, chemokine CCR-2 Accession B15808 secreted proteins involved in biological using assasys known in the art: Methods in Immune, Vascular and processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: Inflammatory disorders angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot; Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related small, Chemokine activities can be determined Autoimmune disorders, chemokine ENA- Accession B15809 secreted proteins involved in biological using assasys known in the art: Methods in Immune, Vascular and 78 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: Inflammatory disorders angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot; Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related small, Chemokine activities can be determined Autoimmune disorders, chemokine Accession B15810 secreted proteins involved in biological using assasys known in the art: Methods in Immune, Vascular and GRObeta processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: Inflammatory disorders angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot; Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related small, Chemokine activities can be determined Autoimmune disorders, chemokine IP-10 Accession B15811 secreted proteins involved in biological using assays known in the art: Methods in Immune, Vascular and processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: Inflammatory disorders angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related small, Chemokine activities can be determined Autoimmune disorders, chemokine Accession B15812 secreted proteins involved in biological using assays known in the art: Methods in Immune, Vascular and SDF1beta processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: Inflammatory disorders angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related small, Chemokine activities can be determined Autoimmune disorders, chemokine GRO Accession B15813 secreted proteins involved in biological using assays known in the art: Methods in Immune, Vascular and alpha processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: Inflammatory disorders angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related small, Chemokine activities can be determined Autoimmune disorders, chemokine Accession B15831 secreted proteins involved in biological using assays known in the art: Methods in Immune, Vascular and MIP1beta processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: Inflammatory disorders angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. A human C-C GeneSeq U.S. Pat. No. 6,096,300 Chemokines are a family of related small, Chemokine activities can be determined Cancer chemokine Accession B07939 secreted proteins involved in biological using assays known in the art: Methods in designated processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: exodus angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq U.S. Pat. No. 6,084,071 Chemokines are a family of related small, Chemokine activities can be determined Chemotaxis, Gene chemokine Accession Y96922 secreted proteins involved in biological using assays known in the art: Methods in Therapy, Wound healing L105_7 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq U.S. Pat. No. 6,084,071 Chemokines are a family of related small, Chemokine activities can be determined Chemotaxis, Gene chemokine Accession Y96923 secreted proteins involved in biological using assays known in the art: Methods in Therapy, Wound healing L105_3 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human secondary GeneSeq WO0038706 Chemokines are a family of related small, Chemokine activities can be determined Cancer, Vascular and lymphoid Accession B01434 secreted proteins involved in biological using assays known in the art: Methods in Immune disorders chemokine (SLC) processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human non-ELR GeneSeq WO0029439 Chemokines are a family of related small, Chemokine activities can be determined Immune and Inflammatory CXC chemokine Accession Y96310 secreted proteins involved in biological using assays known in the art: Methods in disorders, Cancer, H174 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: Haemostatic and angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, thrombolytic activity Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human non-ELR GeneSeq WO0029439 Chemokines are a family of related small, Chemokine activities can be determined Immune and Inflammatory CXC chemokine Accession Y96311 secreted proteins involved in biological using assays known in the art: Methods in disorders, Cancer, IP10 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: haemostatic and angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, thrombolytic activity Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human non-ELR GeneSeq WO0029439 Chemokines are a family of related small, Chemokine activities can be determined Immune and Inflammatory CXC chemokine Accession Y96313 secreted proteins involved in biological using assays known in the art: Methods in disorders, Cancer, Mig processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: haemostatic and angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, thrombolytic activity Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0028035 Chemokines are a family of related small, Chemokine activities can be determined Cancer, wound healing, chemokine Accession Y96280 secreted proteins involved in biological using assays known in the art: Methods in inflammatory and Ckbeta-7 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: immunoregulatory angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, disorders Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0028035 Chemokines are a family of related small, Chemokine activities can be determined Cancer, wound healing, chemokine MIP- Accession Y96281 secreted proteins involved in biological using assays known in the art: Methods in inflammatory and 1alpha processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: immunoregulatory angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, disorders Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human mature GenSeq WO0028035 Chemokines are a family of related small, Chemokine activities can be determined Cancer, wound healing, chemokine Accession Y96282 secreted proteins involved in biological using assays known in the art: Methods in inflammatory and Ckbeta-7 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: immunoregulatory (optionally angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, disorders truncated) Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0018431 Chemokines are a family of related small, Chemokine activities can be determined Soluble CXCR3 chemokine Accession Y79372 secreted proteins involved in biological using assays known in the art: Methods in polypeptides may be receptor CXCR3 processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: useful for inhibiting angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, chemokine activities and Members of this family are involved in a T. N. C. Wells, and C. A. Power. viral infection. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq U.S. Pat. No. 6,043,086 Chemokines are a family of related small, Chemokine activities can be determined Neurological disorders, neurotactin Accession Y53259 secreted proteins involved in biological using assays known in the art: Methods in Immune and respiratory chemokine like processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: disorders domain angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human CC type GeneSeq JP11302298 Chemokines are a family of related small, Chemokine activities can be determined Cancer and infectious chemokine Accession Y57771 secreted proteins involved in biological using assays known in the art: Methods in diseases interleukin C processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified Human CKbeta-9 GeneSeq U.S. Pat. No. 6,153,441 Chemokines are a family of related small, Chemokine activities can be determined Cancer, Auto-immune and Accession B50860 secreted proteins involved in biological using assays known in the art: Methods in inflammatory disorders, processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138: Cardiovascular disorders angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of this family are involved in a T. N. C. Wells, and C. A. Power. similarly diverse range of pathologies © Humana Press Inc., Totowa, NJ including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified Preproapolipoprotein GeneSeq WO9637608 Apoa-1 participates in the reverse Lipid binding activity can be determined Useful for cardiovascular “paris” variant Accession transport of cholesterol from tissues to using assays known in the art, such as, for disorders, cholesterol W08602 the liver for excretion by promoting example, the Cholesterol Efflux Assays of disorders, and cholesterol efflux from tissues and by Takahaski et al., P. N. A. S., Vol. 96, Issue Hyperlipidaemia acting as a cofactor for the lecithin 20, 11358-11363, Sep. 28, 1999. cholesterol acyltransferase (Icat). Preproapolipoprotein 5,721,114 Apoa-1 participates in the reverse Lipid binding activity can be determined Useful for cardiovascular “milano” transport of cholesterol from tissues to using assays known in the art, such as, for disorders, cholesterol variant the liver for excretion by promoting example, the Cholesterol Efflux Assays of disorders, and cholesterol efflux from tissues and by Takahaski et al., P. N. A. S., Vol. 96, Issue Hyperlipidaemia acting as a cofactor for the lecithin 20, 11358-11363, Sep. 28, 1999. cholesterol acyltransferase (Icat). Glycodelin-A; GeneSeq WO9628169 Naturally produced female contraceptive Glycodelin-A activity can be determined Naturally derived Progesterone- Accession that is removed rapidly from the body using the hemizona assay as described in contraceptive useful for associated W00289 following 2-3 days production. Uses Oehninger, S., Coddington, C. C., Hodgen, G. D., the prevention of endometrial include contraception and Seppala, M (1995) Fertil. Steril. pregnancy. protein 63, 377-383. NOGO-A Genbank NOGO polypeptides are potent inhibitors Inhibition of Neurite outgrowth. NOGO-A polypeptide Accession of neurite growth. Antagonists to NOGO polypeptides may antagonists are useful for CAB99248 promote the outgrowth of neurites, thus the promotion of neural inducing regeneration of neurons. growth, which could be useful in the treatment of neural disorders and dysfunction due to degenerative diseases or trauma; useful in the treatment of neoplastic diseases of the CNS; induce regeneration of neurons or to promote the structural plasticity of the CNS. NOGO-B Genbank NOGO polypeptides are potent inhibitors Inhibition of Neurite outgrowth. NOGO-B polypeptide Accession of neurite growth. Antagonists to NOGO polypeptides may antagonists are useful for CAB99249 promote the outgrowth of neurites, thus the promotion of neural inducing regeneration of neurons. growth, which could be useful in the treatment of neural disorders and dysfunction due to degenerative diseases or trauma; useful in the treatment of neoplastic diseases of the CNS; induce regeneration of neurons or to promote the structural plasticity of the CNS. NOGO-C Genbank NOGO polypeptides are potent inhibitors Inhibition of Neurite outgrowth. NOGO-C polypeptide Accession of neurite growth. Antagonists to NOGO polypeptides may antagonists are useful for CAB99250 promote the outgrowth of neurites, thus the promotion of neural inducing regeneration of neurons. growth, which could be useful in the treatment of neural disorders and dysfunction due to degenerative diseases or trauma; useful in the treatment of neoplastic diseases of the CNS; induce regeneration of neurons or to promote the structural plasticity of the CNS. NOGO-66 Genbank NOGO polypeptides are potent inhibitors Inhibition of Neurite outgrowth by NOGO-66 receptor Receptor Accession of neurite growth, and are thought to mediating the biological effects of NOGO polypeptides are useful for AAG53612 mediate their effects through the NOGO- polypeptides. Soluble NOGO-66 receptor the promotion of neural 66 Receptor. polypeptides may promote the outgrowth growth, which could be of neurites, thus inducing regeneration of useful in the treatment of neurons. neural disorders and dysfunction due to degenerative diseases or trauma; useful in the treatment of neoplastic diseases of the CNS; induce regeneration of neurons or to promote the structural plasticity of the CNS. Antibodies specific U.S. Pat. No. 5,416,197 These antibodies are useful for the Collapsin activity, which is thought to Useful for the promotion of for collapsin promotion of neurite outgrowth inhibit the outgrowth of neurites, can be neural growth, which could assayed in the presence of antibodies be useful in the treatment specific for collapsing using assays known of neural disorders and in the art, such as, for example, the dysfunction due to collapse assay disclosed by Luo et al., degenerative diseases or Cell 1993 Oct 22; 75(2): 217-27 trauma. Humanized Anti- WO9845331 These agents have anti-inflammatory and VEGF activity can be determined using Promotion of growth and VEGF Antibodies, anti-cancer applications assays known in the art, such as those proliferation of cells, such and fragments disclosed in International Publication No. as vascular endothelial thereof WO0045835, for example. cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer Humanized Anti- WO0029584 These agents have anti-inflammatory and VEGF activity can be determined using Promotion of growth and VEGF Antibodies, anti-cancer applications assays known in the art, such as those proliferation of cells, such and fragments disclosed in International Publication No. as vascular endothelial thereof WO0045835, for example. cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer Membrane bound GeneSeq. WO9963088 Cancer, Immune Disorders These proteins can be used for linking Activities can be proteins Accession bioactive molecules to cells and for determined using assay Y66631-Y66765 modulating biological activities of cells, known in the art, suchas, using the polypeptides for specific for example, the assays targeting. The polypeptide targeting can disclosed in International be used to kill the target cells, e.g. for the Publication No. treatment of cancers. These proteins are WO0121658. useful for the treatment of immune system disorders. Secreted and GenSeq WO0053756 Cancer, Immune Disorders These proteins can be used for linking Activities can be Transmembrane Accession bioactive molecules to cells and for determined using assay polypeptides B44241-B44334 modulating biological activities of cells, known in the art, suchas, using the polypeptides for specific for example, the assays targeting. The polypeptide targeting can disclosed in International be used to kill the target cells, e.g. for the Publication No. treatment of cancers. These proteins are WO0121658 useful for the treatment of immune system disorders. Secreted and GeneSeq WO9946281 Cancer, Immune Disorders These proteins can be used for linking Activities can be Transmembrane Accession bioactive molecules to cells and for determined using assay polypeptides Y41685-Y41774 modulating biological activities of cells, known in the art, suchas, using the polypeptides for specific for example, the assays targeting. The polypeptide targeting can disclosed in International be used to kill the target cells, e.g. for the Publication No. treatment of cancers. These proteins are WO0121658 useful for the treatment of immune system disorders.

Conjugation and Coupling

The present invention provides therapeutic agents comprising an elastic peptide component and a therapeutic component, such as therapeutic proteins listed in herein, including Table 1, as well as a GLP-1 receptor agonists, insulin, Factor VII/VIIa, and functional analogs as described. Such agents may be prepared by recombinant technology and/or chemical coupling (e.g., conjugation).

A recombinantly-produced elastic peptide fusion protein, in accordance with certain embodiments of the invention, includes the elastic peptide component and the therapeutic component associated with one another by genetic fusion. For example, the fusion protein may be generated by translation of a polynucleotide encoding the therapeutic component cloned in-frame with the elastic peptide component (or vice versa). Such an elastic peptide fusion protein may contain one or more copies of the therapeutic component attached to the N-terminus and/or the C-terminus of the elastic peptide component. In some embodiments, the therapeutic proteinacious component is attached to both the N- and C-terminus of the elastic peptide component and the fusion protein may contain one or more equivalents of the therapeutic component on either or both ends of the elastic peptide component.

In certain embodiments, the elastic peptide component and the therapeutic components can be fused using a linker peptide of various lengths to provide greater physical separation and allow more spatial mobility between the fused portions, and thus maximize the accessibility of the therapeutic component, for instance, for binding to its cognate receptor. The linker peptide may consist of amino acids that are flexible or more rigid. For example, a flexible linker may include amino acids having relatively small side chains, and which may be hydrophilic. Without limitation, the flexible linker may contain a stretch of glycine and/or serine residues. More rigid linkers may contain, for example, more sterically hindering amino acid side chains, such as (without limitation) tyrosine or histidine. The linker may be less than about 50, 40, 30, 20, 10, or 5 amino acid residues. The linker can be covalently linked to and between an elastic peptide component and a therapeutic component, for example, via recombinant fusion.

The linker or peptide spacer may be protease-cleavable or non-cleavable. By way of example, cleavable peptide spacers include, without limitation, a peptide sequence recognized by proteases (in vitro or in vivo) of varying type, such as Tev, thrombin, factor Xa, plasmin (blood proteases), metalloproteases, cathepsins (e.g., GFLG, etc.), and proteases found in other corporeal compartments. In some embodiments employing cleavable linkers, the fusion protein (“the therapeutic agent”) may be inactive, less active, or less potent as a fusion, which is then activated upon cleavage of the spacer in vivo. Alternatively, where the therapeutic agent is sufficiently active as a fusion, a non-cleavable spacer may be employed. The non-cleavable spacer may be of any suitable type, including, for example, non-cleavable spacer moieties having the formula [(Gly)n-Ser]m (SEQ ID NO.: 22) where n is from 1 to 4, inclusive, and m is from 1 to 4, inclusive. Alternatively, a short elastic peptide sequence different than the backbone elastic peptide could be employed instead of a linker or spacer, while accomplishing the necessary effect.

In still other embodiments, the therapeutic agent is a recombinant fusion having a therapeutic component flanked on each terminus by an elastic peptide component. At least one of said elastic peptide components may be attached via a cleavable spacer, such that the therapeutic component is inactive, but activated in vivo by proteolytic removal of a single elastic peptide component. The resulting single elastic peptide fusion being active, and having an enhanced half-life (or other property described herein) in vivo.

In other embodiments, the present invention provides chemical conjugates of the elastic peptide component and the therapeutic component. The conjugates can be made by chemically coupling an elastic peptide component to a therapeutic component by any number of methods well known in the art (See e.g. Nilsson et al., 2005, Ann Rev Biophys Bio Structure 34: 91-118). In some embodiments, the chemical conjugate can be formed by covalently linking the therapeutic component to the elastic peptide component, directly or through a short or long linker moiety, through one or more functional groups on the therapeutic proteinacious component, e.g., amine, carboxyl, phenyl, thiol or hydroxyl groups, to form a covalent conjugate. Various conventional linkers can be used, e.g., diisocyanates, diisothiocyanates, carbodiimides, bis(hydroxysuccinimide) esters, maleimide-hydroxysuccinimide esters, glutaraldehyde and the like.

Non-peptide chemical spacers can additionally be of any suitable type, including for example, by functional linkers described in Bioconjugate Techniques, Greg T. Hermanson, published by Academic Press, Inc., 1995, and those specified in the Cross-Linking Reagents Technical Handbook, available from Pierce Biotechnology, Inc. (Rockford, Ill.), the disclosures of which are hereby incorporated by reference, in their respective entireties. Illustrative chemical spacers include homobifunctional linkers that can attach to amine groups of Lys, as well as heterobifunctional linkers that can attach to Cys at one terminus, and to Lys at the other terminus.

In certain embodiments, relatively small ELP components (e.g., ELP components of less than about 30 kDa, 25 kDa, 20 kDa, 15 kDa, or 10 kDa), that do not transition at room temperature (or human body temperature, e.g., Tt>37° C.), are chemically coupled or crosslinked. For example, two relatively small ELP components, having the same or different properties, may be chemically coupled. Such coupling, in some embodiments, may take place in vivo, by the addition of a single cysteine residue at or around the C-terminus of the ELP. Such ELP components may each be fused to one or more therapeutic components, so as to increase activity or avidity at the target.

Polynucleotides, Vectors, and Host Cells

In another aspect, the invention provides polynucleotides comprising a nucleotide sequence encoding the therapeutic agent of the invention. Such polynucleotides further comprise, in addition to sequences encoding the elastic peptide and therapeutic components, one or more expression control elements. For example, the polynucleotide, may comprise one or more promoters or transcriptional enhancers, ribosomal binding sites, transcription termination signals, and polyadenylation signals, as expression control elements. The polynucleotide may be inserted within any suitable vector, which may be contained within any suitable host cell for expression.

A vector comprising the polynucleotide can be introduced into a cell for expression of the therapeutic agent. The vector can remain episomal or become chromosomally integrated, as long as the insert encoding the therapeutic agent can be transcribed. Vectors can be constructed by standard recombinant DNA technology. Vectors can be plasmids, phages, cosmids, phagemids, viruses, or any other types known in the art, which are used for replication and expression in prokaryotic or eukaryotic cells. It will be appreciated by one of skill in the art that a wide variety of components known in the art (such as expression control elements) may be included in such vectors, including a wide variety of transcription signals, such as promoters and other sequences that regulate the binding of RNA polymerase onto the promoter. Any promoter known to be effective in the cells in which the vector will be expressed can be used to initiate expression of the therapeutic agent. Suitable promoters may be inducible or constitutive. Examples of suitable promoters include the SV40 early promoter region, the promoter contained in the 3′ long terminal repeat of Rous sarcoma virus, the HSV-1 (herpes simplex virus-1) thymidine kinase promoter, the regulatory sequences of the metallothionein gene, etc., as well as the following animal transcriptional control regions, which exhibit tissue specificity and have been utilized in transgenic animals: elastase I gene control region which is active in pancreatic acinar cells; insulin gene control region which is active in pancreatic beta cells, immunoglobulin gene control region which is active in lymphoid cells, mouse mammary tumor virus control region which is active in testicular, breast, lymphoid and mast cells, albumin gene control region which is active in liver, alpha-fetoprotein gene control region which is active in liver, alpha 1-antitrypsin gene control region which is active in the liver, beta-globin gene control region which is active in erythroid cells, myelin basic protein gene control region which is active in oligodendrocyte cells in the brain, myosin light chain-2 gene control region which is active in skeletal muscle, and gonadotropin releasing hormone gene control region which is active in the hypothalamus.

Pharmaceutical Compositions

The present invention further provides pharmaceutical compositions comprising the therapeutic agents of the invention (as described above) together with a pharmaceutically acceptable carrier or excipient. Such pharmaceutical compositions may be employed in the methods of treatment as described above, for each of the therapeutic proteins, e.g., the therapeutic proteins listed in Table 1, GLP-1 receptor agonists, insulin, and Factor VII/VIIa embodiments.

The therapeutic agents of the invention may overcome certain deficiencies of peptide agents when administered (e.g., parenterally), including in some embodiments, the limitation that such peptides may be easily metabolized by plasma proteases or cleared from circulation by kidney filtration. Traditionally, the oral route of administration of peptide agents may also be problematic, because in addition to proteolysis in the stomach, the high acidity of the stomach destroys such peptide agents before they reach their intended target tissue. Peptides and peptide fragments produced by the action of gastric and pancreatic enzymes are cleaved by exo and endopeptidases in the intestinal brush border membrane to yield di- and tripeptides, and even if proteolysis by pancreatic enzymes is avoided, polypeptides are subject to degradation by brush border peptidases. Any of the peptide agents that survive passage through the stomach are further subjected to metabolism in the intestinal mucosa where a penetration barrier prevents entry into the cells. In certain embodiments, the therapeutic agents of the invention may overcome such deficiencies, and provide compositional forms having enhanced efficacy, bioavailability, therapeutic half-life, persistence, degradation assistance, etc. The therapeutic agents of the invention thus include oral and parenteral dose forms, as well as various other dose forms, by which peptide agents can be utilized in a highly effective manner. For example, in some embodiments, such agents may achieve high mucosal absorption, and the concomitant ability to use lower doses to elicit an optimum therapeutic effect.

The therapeutic agents of the present invention may be administered in smaller doses and/or less frequently than unfused or unconjugated counterparts. While one of skill in the art can determine the desirable dose in each case, a suitable dose of the therapeutic agent for achievement of therapeutic benefit, may, for example, be in a range of about 1 microgram (μg) to about 100 milligrams (mg) per kilogram body weight of the recipient per day, preferably in a range of about 10 μg to about 50 mg per kilogram body weight per day and most preferably in a range of about 10 μg to about 50 mg per kilogram body weight per day. The desired dose may be presented as one dose or two or more sub-doses administered at appropriate intervals throughout the day. These sub-doses can be administered in unit dosage forms, for example, containing from about 10 μg to about 1000 mg, preferably from about 50 μg to about 500 mg, and most preferably from about 50 μg to about 250 mg of active ingredient per unit dosage form. Alternatively, if the condition of the recipient so requires, the doses may be administered as a continuous infusion.

The mode of administration and dosage forms will of course affect the therapeutic amount of the peptide active therapeutic agent that is desirable and efficacious for a given treatment application. For example, orally administered dosages can be at least twice, e.g., 2-10 times, the dosage levels used in parenteral administration methods.

The therapeutic agents of the invention may be administered per se as well as in various forms including pharmaceutically acceptable esters, salts, and other physiologically functional derivatives thereof. The present invention also contemplates pharmaceutical formulations, both for veterinary and for human medical use, which include therapeutic agents of the invention. In such pharmaceutical and medicament formulations, the therapeutic agents can be used together with one or more pharmaceutically acceptable carrier(s) therefore and optionally any other therapeutic ingredients. The carrier(s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not unduly deleterious to the recipient thereof. The therapeutic agents are provided in an amount effective to achieve the desired pharmacological effect, as described above, and in a quantity appropriate to achieve the desired daily dose.

The formulations of the therapeutic agent include those suitable for parenteral as well as non-parenteral administration, and specific administration modalities include oral, rectal, buccal, topical, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdermal, intrathecal, intra-articular, intra-arterial, sub-arachnoid, bronchial, lymphatic, vaginal, and intra-uterine administration. Formulations suitable for oral and parenteral administration are preferred.

When the therapeutic agent is used in a formulation including a liquid solution, the formulation advantageously can be administered orally or parenterally. When the therapeutic agent is employed in a liquid suspension formulation or as a powder in a biocompatible carrier formulation, the formulation may be advantageously administered orally, rectally, or bronchially.

When the therapeutic agent is used directly in the form of a powdered solid, the active agent can be advantageously administered orally. Alternatively, it may be administered bronchially, via nebulization of the powder in a carrier gas, to form a gaseous dispersion of the powder which is inspired by the patient from a breathing circuit comprising a suitable nebulizer device.

The formulations comprising the therapeutic agent of the present invention may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. Such methods generally include the step of bringing the therapeutic agents into association with a carrier which constitutes one or more accessory ingredients. Typically, the formulations are prepared by uniformly and intimately bringing the therapeutic agent into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into dosage forms of the desired formulation.

Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active ingredient as a powder or granules; or a suspension in an aqueous liquor or a non-aqueous liquid, such as a syrup, an elixir, an emulsion, or a draught.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, with the therapeutic agent being in a free-flowing form such as a powder or granules which optionally is mixed with a binder, disintegrant, lubricant, inert diluent, surface active agent, or discharging agent. Molded tablets comprised of a mixture of the powdered peptide active therapeutic agent-elastic peptide construct(s) with a suitable carrier may be made by molding in a suitable machine.

A syrup may be made by adding the peptide active therapeutic agent-ELF construct(s) to a concentrated aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredient(s). Such accessory ingredient(s) may include flavorings, suitable preservative, agents to retard crystallization of the sugar, and agents to increase the solubility of any other ingredient, such as a polyhydroxy alcohol, for example glycerol or sorbitol.

Formulations suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the therapeutic agent, which preferably is isotonic with the blood of the recipient (e.g., physiological saline solution). Such formulations may include suspending agents and thickening agents or other microparticulate systems which are designed to target the peptide active therapeutic agent to blood components or one or more organs. The formulations may be presented in unit-dose or multi-dose form.

Nasal spray formulations comprise purified aqueous solutions of the therapeutic agent with preservative agents and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal mucus membranes.

Formulations for rectal administration may be presented as a suppository with a suitable carrier such as cocoa butter, hydrogenated fats, or hydrogenated fatty carboxylic acid.

Topical formulations comprise the therapeutic agent dissolved or suspended in one or more media, such as mineral oil, petroleum, polyhydroxy alcohols, or other bases used for topical pharmaceutical formulations.

In addition to the aforementioned ingredients, the formulations of this invention may further include one or more accessory ingredient(s) selected from diluents, buffers, flavoring agents, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like.

The features and advantages of the present invention are more fully shown with respect to the following non-limiting examples.

EXAMPLES Example 1 Construction of Various ELP Component Constructs

Cloning steps were conducted in Escherichia coli strain XL1-Blue (rec A1, endA1, gyrA96, thi-1, hsdR17 (r_(k) ⁻, m_(k)+), supE44, relA1, lac[F′, proAB, /αcl^(q)ZΔM15, Tn10 (Tet^(r))] (Stratagene La Jolla, Calif.). pUC19 (NEB, Beverly, Mass.) was used as the cloning vector for the ELP construction (Meyer and Chilkoti, Nat. Biotechnol., 17(11):1112-5, 1999). Modified forms of pET15b and pET24d vectors (Novagen) were used to express ELP and ELP-fusion proteins in BL21 Star (DE3) strain (F⁻, ompT, hsdS_(B) (r_(B) ⁻ m_(B) ⁻), gal, dcm, rne131, (DE3)) (Invitrogen Carlsbed, Calif.) or BLR(DE3) (F⁻, ompT, hsdS_(B) (r_(B) ⁻ m_(B) ⁻), gal, dcm, Δ(srl-recA) 306::Tn10(TcR)(DE3)) (Novagen Madison, Wis.). Synthetic DNA oligos were purchased from Integrated DNA Technologies, Coralville, Iowa. All vector constructs were made using standard molecular biology protocols (e.g., Current Protocols in Molecular Biology, ed. Ausubel, et al., 1995).

Construction of ELP1 [V₅A₂G₃] Gene Series

The ELP1 [V₅A₂G₃] series designate polypeptides containing multiple repeating units of the pentapeptide VPGXG (SEQ ID NO: 3), where X is valine, alanine, and glycine at a relative ratio of 5:2:3.

The ELP1 [V₅A₂G₃] series monomer, ELP1 [V₅A₂G₃-10], was created by annealing four 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with EcoRI and HindIII compatible ends (Meyer and Chilkoti, Nat. Biotechnol., 17(11):1112-5, 1999). The oligos were annealed in a 1 μM mixture of the four oligos in 50 μl IX ligase buffer (Invitrogen) to 95° C. in a heating block than the block was allowed to cool slowly to room temperature. The ELP1 [V₅A₂G₃-10]/EcoRI-HindIII DNA segment was ligated into a pUC19 vector digested with EcoRI and HindIII and CIAP dephosphorylated (Invitrogen) to form pUC19-ELP1 [V₅A₂G₃-10]. Building of the ELP1 [V₅A₂G₃] series library began by inserting ELP1 [V₅A₂G₃-10] Pf/MI/BgII fragment from pUC19-ELP1 [V₅A₂G₃-10] into pUC19-ELP1 [V₅A₂G₃-10] linearized with Pf/MI and dephosphorylated with CIAP to create pUC19-ELP1 [V₅A₂G₃-20]. pUC19-ELP1 [V₅A₂G₃-20] was then built up to pUC19-ELP1 [V₅A₂G₃-30] and pUC19-ELP1 [V₅A₂G₃-40] by ligating ELP1 [V₅A₂G₃-10] or ELP1 [V₅A₂G₃-20] Pf/MI/BgII fragments respectively into Pf/MI digested pUC19-ELP1 [V₅A₂G₃-20]. This procedure was used to expand the ELP1 [V₅A₂G₃] series to create pUC19-ELP1 [V₅A₂G₃-60], pUC19-ELP1 [V₅A₂G₃-90] and pUC19-ELP1 [V₅A₂G₃-180] genes.

Construction of ELP1 [K₁V₂F₁] Gene Series

The ELP1 [K₁V₂F₁] series designate polypeptides containing multiple repeating units of the pentapeptide VPGXG (SEQ ID NO: 3), where X is lysine, valine, and phenylalanine at a relative ratio of 1:2:1.

The ELP1 [K₁V₂F₁] series monomer, ELP1 [K₁V₂F₁-4], was created by annealing two 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with EcoRI and HindIII compatible ends (Meyer and Chilkoti, 1999). The oligos were annealed in a 1 μM mixture of the four oligos in 50 μl 1× ligase buffer (Invitrogen) to 95° C. in a heating block then the block was allowed to cool slowly to room temperature. The ELP1 [K₁V₂F₁-4]/EcoRI-HindIII DNA segment was ligated into a pUC19 vector digested with EcoRI and HindIII and CIAP dephosphorylated (Invitrogen) to form pUC19-ELP1 [K₁V₂F₁-4]. Building of the ELP1 [K₁V₂F₁] series library began by inserting ELP1 [K₁V₂F₁-4] Pf/MI/BgII fragment from pUC19-ELP1 [K₁ V₂F₁-4] into pUC19-ELP1 [K₁V₂F₁-4] linearized with Pf/M1 and dephosphorylated with CIAP to create pUC19-ELP1 [K₁V₂F₁-8]. Using the same procedure the ELP1 [K₁V₂F₁] series was doubled at each ligation to form pUC19-ELP1 [K₁V₂F₁-16], pUC19-ELP1 [K₁V₂F₁-32], pUC19-ELP1 [K₁ V₂F₁-64] and pUC19-ELP1 [K₁V₂F₁-128].

Construction of ELP1 [K₁V₇F₁] Gene Series

The ELP1 [K₁V₇F₁] series designate polypeptides containing multiple repeating units of the pentapeptide VPGXG (SEQ ID NO: 3), where X is lysine, valine, and phenylalanine at a relative ratio of 1:7:1.

The ELP1 [K₁V₇F₁] series monomer, ELP1 [K₁V₇F₁-9], was created by annealing four 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with Pf/MI and HindIII compatible ends. The ELP1 [K₁V₇F₁-9] DNA segment was than ligated into Pf/M1/HindIII dephosphorylated PUC19-ELP1 [V₅A₂G₃-180] vector thereby substituting ELP1 [V₅A₂G₃-180] for ELP1 [K₁V₇F₁-9] to create the pUC19-ELP1 [K₁V₇F₁-9] monomer. The ELP1 [K₁V₇F₁] series was expanded in the same manner as the ELP1 [K₁V₂F₁] series to create pUC19-ELP1 [K₁V₇F₁-18], PUC19-ELP1 [K₁V₇F₁-36], pUC19-ELP1 [K₁V₇F₁-72] and pUC19-ELP1 [K₁V₇F₁-144].

Construction of ELP1 [V] Gene Series

The ELP1 [V] series designate polypeptides containing multiple repeating units of the pentapeptide VPGXG (SEQ ID NO: 3), where X is exclusively valine.

The ELP1 [V] series monomer, ELP1 [V-5], was created by annealing two 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with EcoRI and HindIII compatible ends. The ELP1 [V-5] DNA segment was than ligated into EcoRI/HindIII dephosphorylated pUC19 vector to create the pUC19-ELP1 [V-5] monomer. The ELP1 [V] series was created in the same manner as the ELP1 [V₅A₂G₃] series, ultimately expanding pUC19-ELP1 [V-5] to pUC19-ELP1 [V-60] and pUC19-ELP1 [V-120].

Construction of ELP2 Gene Series

The ELP2 series designate polypeptides containing multiple repeating units of the pentapeptide AVGVP.

The ELP2 series monomer, ELP2 [5], was created by annealing two 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with EcoRI and HindIII compatible ends. The ELP2 [5] DNA segment was than ligated into EcoRI/HindIII dephosphorylated pUC19 vector to create the pUC19-ELP2[5] monomer. The ELP2 series was expanded in the same manner as the ELP1 [K₁V₂F₁] series to create pUC19-ELP2[10], pUC19-ELP2 [30], pUC19-ELP2 [60] and pUC19-ELP2 [120].

Construction of ELP3 [V] Gene Series

The ELP3 [V] series designate polypeptides containing multiple repeating units of the pentapeptide IPGXG (SEQ ID NO: 5), where X is exclusively valine.

The ELP3 [V] series monomer, ELP3 [V-5], was created by annealing two 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with PfLM1 amino terminal and GGC carboxyl terminal compatible ends due to the lack of a convenient carboxyl terminal restriction site but still enable seamless addition of the monomer. The ELP3 [V-5] DNA segment was then ligated into PfIM1/BgII dephosphorylated pUC19-ELP4[V-5], thereby substituting ELP4 [V-5] for ELP3 [V-5] to create the pUC19-ELP3 [V-5] monomer. The ELP3 [V] series was expanded by ligating the annealed ELP3 oligos into pUC19-ELP3[V-5] digested with PfIMI. Each ligation expands the ELP3 [V] series by 5 to create ELP3 [V-10], ELP3 [V-15], etc.

Construction of the ELP4 [V] Gene Series

The ELP4 [V] series designate polypeptides containing multiple repeating units of the pentapeptide LPGXG (SEQ ID NO: 7), where X is exclusively valine.

The ELP4 [V] series monomer, ELP4 [V-5], was created by annealing two 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with EcoRI and HindIII compatible ends. The ELP4 [V-5] DNA segment was than ligated into EcoRI/HindIII dephosphorylated pUC19 vector to create the pUC19-ELP4[V-5] monomer. The ELP4 [V] series was expanded in the same manner as the ELP1 [K₁V₂F₁] series to create pUC19-ELP4[V-10], pUC19-ELP4[V-30], pUC19-ELP4[V-60] and pUC19-ELP4[V-120].

The ELP genes were also inserted into other vectors such as pET15b-SD0, pET15b-SD3, pET15b-SD5, pET15b-SD6, and pET24d-SD21. The pET vector series are available from Novagen, San Diego, Calif.

The pET15b-SD0 vector was formed by modifying the pET15b vector using SD0 double-stranded DNA segment containing the multicloning restriction site (SacI-NdeI-NcoI-XhoI-SnaBI-BamHI). The SD0 double-stranded DNA segment had XbaI and BamHI compatible ends and was ligated into XbaI/BamHI linearized and 5′-dephosphorylated pET15b to form the pet15b-SD0 vector.

The pET15b-SD3 vector was formed by modifying the pET15b-SD0 vector using SD3 double-stranded DNA segment containing a SfiI restriction site upstream of a hinge region-thrombin cleavage site followed by the multicloning site (NdeI-NcoI-XhoI-SnaBI-BamHI). The SD3 double-stranded DNA segment had SacI and NdeI compatible ends and was ligated into SacI/NdeI linearized and 5′-dephosphorylated pET15b-SD0 to form the pET15b-SD3 vector.

The pET15b-SD5 vector was formed by modifying the pET15b-SD3 vector using the SD5 double-stranded DNA segment containing a SfiI restriction site upstream of a thrombin cleavage site followed by a hinge and the multicloning site (NdeI-NcoI-XhoI-SnaBI-BamHI). The SD5 double-stranded DNA segment had SfiI and NdeI compatible ends and was ligated into SfiI/NdeI linearized and 5′-dephosphorylated pET15b-SD3 to form the pET15b-SD5 vector.

The pET15b-SD6 vector was formed by modifying the pET15b-SD3 vector using the SD6 double-stranded DNA segment containing a SfiI restriction site upstream of a linker region-TEV cleavage site followed by the multicloning site (NdeI-NcoI-XhoI-SnaBI-BamHÏ). The SD6 double-stranded DNA segment had SfiI and NheI compatible ends and was ligated into SfiI/NdeI linearized and 5′-dephosphorylated pET15b-SD3 to form the pET15b-SD6 vector.

The pET24d-SD21 vector was formed by modifying the pET24d vector using the SD21 double-stranded DNA segment with NcoI and NheI compatible ends. The SD21 double-stranded DNA segment was ligated into NcoI/NheI linearized and 5′ dephosphorylated pET24d to create the pET24d-SD21 vector, which contained a new multi-cloning site NcoI-SfiI-NheI-BamHI-EcoRI-SacI-SalI-HindIII-NotI-XhoI with two stop codons directly after the SfiI site for insertion and expression of ELP with the minimum number of extra amino acids.

The pUC19-ELP1 [V₅A₂G₃-60], pUC19-ELP1 [V₅A₂G₃-90], and pUC19-ELP1 [V₅A₂G₃-180] plasmids produced in XL1-Blue were digested with Pf/MI and BgII, and the ELP-containing fragments were ligated into the SfiI site of the pET15b-SD3 expression vector as described hereinabove to create pET15b-SD3-ELP1 [V₅A₂G₃-60], pET15b-SD5-ELP1 [V₅A₂G₃-90] and pET15b-SD5-ELP1 [V₅A₂G₃-180], respectively.

The pUC19-ELP1 [V₅A₂G₃-90], pUC19-ELP1 [V₅A₂G₃-180], pUC19-ELP1 [V-60] and pUC19-ELP1 [V-120] plasmids produced in XL1-Blue were digested with Pf/MI and BgII, and the ELP-containing fragments were ligated into the SfiI site of the pET15b-SD5 expression vector as described hereinabove to create pET15b-SD5-ELP1 [V₅A₂G₃-90], pET15b-SD5-ELP1 [V₅A₂G₃-180], pET15b-SD5-ELP1 [V-60] and pET15b-SD5-ELP1 [V-120], respectively.

The pUC19-ELP1 [V₅A₂G₃-90] plasmid produced in XL1-Blue was digested with Pf/MI and BgII, and the ELP-containing fragment was ligated into the SfiI site of the pET15b-SD6 expression vector as described hereinabove to create pET15b-SD6-ELP1 [V₅A₂G₃-90].

The pUC19-ELP1 [K₁V₂F₁-64], and pUC19-ELP1 [K₁V₂F₁-128] plasmids produced in XL1-Blue were digested with Pf/MI and BgII, and the ELP-containing fragments were ligated into the SfiI site of the pET24d-SD21 expression vector as described hereinabove to create pET24d-SD21-ELP1 [K₁V₂F₁-64] and pET24d-SD21-ELP1 [K₁V₂F₁-128], respectively.

The pUC19-ELP1 [K₁V₇F₁-72] and pUC19-ELP1 [K₁V₇F₁-144] plasmids produced in XL1-Blue were digested with Pf/MI and BgII, and the ELP-containing fragments were ligated into the SfiI site of the pET24d-SD21 expression vector as described hereinabove to create pET24d-SD21-ELP1 [K₁V₇F₁-72], pET24d-SD21-ELP1 [K₁V₇F₁-144], respectively.

The pUC19-ELP2[60] and pUC19-ELP2[120] plasmids produced in XL1-Blue were digested with NcoI and HindIII, and the ELP-containing fragments were ligated into the NcoI and HindIII sites of the pET24d-SD21 expression vector as described hereinabove to create pET24d-SD21-ELP2[60], pET24d-SD21-ELP2[120], respectively.

The pUC19-ELP4[V-60] and pUC19-ELP4[V-120] plasmids produced in XL1-Blue were digested with NcoI and HindIII, and the ELP-containing fragments were ligated into the NcoI and HindIII sites of the pET24d-SD21 expression vector as described hereinabove to create pET24d-SD21-ELP4[V-60], pET24d-SD21-ELP4[V-120], respectively.

Example 2 Isolation and Purification of Fusion Proteins Containing Insulin a peptide (InsA)

ELP-InsA fusion proteins included the following:

Insulin A peptide and ELP1 [V-60] polypeptide with an enterokinase protease cleavage site therebetween.

Insulin A peptide and ELP1 [V₅A₂G₃-90] polypeptide with an enterokinase protease cleavage site therebetween.

Insulin A peptide and ELP1 [V-120] polypeptide with an enterokinase protease cleavage site therebetween.

Insulin A peptide and ELP1 [V₅A₂G₃-180] polypeptide with an enterokinase protease cleavage site therebetween.

A single colony of E. coli strain BLR (DE3) (Novagen) containing the respective ELP-InsA fusion protein was inoculated into 5 ml CircleGrow (Q-BIOgene, San Diego, Calif.) supplemented with 100 μg/ml ampicillin (Sigma) and grown at 37° C. with shaking at 250 rpm for 5 hours. The 5 ml culture was then inoculated into a 500 ml culture and allowed to grow at 25° C. for 16 hours before inducing with 1 mM IPTG for 4 hours at 25° C. The culture was harvested and suspended in 40 ml 20 mM Tris-HCl pH 7.4, 50 mM NaCl, 1 mM DTT and 1 Complete EDTA free Protease inhibitor pellet (Roche, Indianapolis, Ind.). Cells were lysed by ultrasonic disruption on ice for 3 minutes, which consisted of 10 seconds bursts at 35% power separated by 30 second cooling down intervals. Cell debris was removed by centrifugation at 20,000 g, 4° C. for 30 minutes.

Inverse phase transition was induced by adding NaCl to the cell lysate at room temperature to achieve a final concentration of 1.0 M therein, followed by centrifugation at 20,000 g for 15 minutes at room temperature. The resulting pellet contained the respective ELP-InsA fusion protein and non-specifically NaCl precipitated proteins.

The pellet was re-suspended in 40 ml ice-cold ml 20 mM Tris-HCl pH 7.4, 50 mM NaCl, 1 mM DTT and re-centrifuged at 20,000 g, 4° C. for 15 minutes to remove the non-specifically NaCl precipitated proteins. The inverse transition cycle was repeated two additional times to increase the purity of the respective ELP-InsA fusion protein and reduce the final volume to 0.5 ml.

Example 3 Half-Life of ELP1

The pharmacokinetics of ELP1 were determined by intravenously administering [¹⁴C]ELP1 to nude mice (Balb/c nu/nu) bearing a leg/flank FaDu xenograft and collecting blood samples at various time intervals after administration. The blood pharmacokinetics exhibited a characteristic distribution and elimination response for large macromolecules, which was well described by a bi-exponential process.

The plasma concentration time-course curve was fit to the analytical solution of a two-compartment model to approximate both an elimination and distribution response. Certain pharmakinetic parameters are shown in Table 1 below. The distribution volume of the ELP (1.338 μl) was nearly identical to the hypothetical plasma volume of 1.363 μl (Barbee, R. W., et al., Am. J. Physio. 263(3) (1992) R728-R733), indicating that the ELP did not rapidly distribute or bind to specific organs and tissues directly after administration. The AUC is a measure of the cumulative exposure to ELP in the central compartment or the blood plasma. The body clearance is defined as the rate of ELP elimination in the body relative to its plasma concentration and is the summation of clearance through all organs including the kidney, liver and others.

TABLE 1 Pharmacokinetic parameters calculated for [¹⁴C]ELP1 k₁ k₂ k_(e) V_(d) AUC (mg Cl_(B) (hr⁻¹) (hr⁻¹) (hr⁻¹) (μL) ELP hr/ml) (μL/hr) ELP1-150 3.54 1.99 0.24 1,338 7.1 317

The mass transfer rate constants are from a standard two-compartment model (k₁; from central to peripheral compartment; k₂, from peripheral to central compartment; and k_(e), elimination from central compartment). The distribution volume (V_(d)), central compartment concentration time-course area under the curve (AUC) and body clearance (Cl_(B)) are displayed. Data are shown as the mean values (n=5, except V_(d) and initial plasma concentration (C_(O)) was calculated from a similar cohort with n=3).

Example 4 Biodistribution of ELPs in Nude Mice ¹⁴C Labeled ELP1-150 and/or ¹⁴C Labeled ELP2-160

¹⁴C labeled ELP1-150 and/or ¹⁴C labeled ELP2-160 were administered to nude mice with a FaDu tumor (mean+/−SD, n=6). The tumor was heated post administration of the ELP in a water bath at 41.5° C. The distribution was highest to the organs with the highest blood content: liver, kidneys, spleen, and lungs.

¹⁴C labeled ELP2-[V₁A₈G₇-160]

¹⁴C labeled ELP2-[V₁A₈G₇-160] (T_(t)>60° C.) was administered to nude mice for a plasma concentration of 15 μM. ELP concentrations were determined following 1 hour of heating (41° C.) of an implanted FaDu tumor, located in the right hind leg of the nude mouse. Data are shown as the mean, plus the 95% confidence interval. N=6.

ELP concentration was measured 1.5 hours following systemic administration of ¹⁴C labeled ELP2-[V₁A₈G₇-160]. The highest distribution is seen in organs with the highest blood content: liver, kidneys, spleen, and lungs.

Example 5 Exendin-4 ELP Fusion

The DNA sequence for Exendin-4 (Ex-4) (SEQ ID NO: 14) was reverse translated from the amino acid sequence using codons optimized for E. coli expression. The DNA sequence encoding Exendin-4 was constructed by annealing together synthetic oligonucleotides with overhanging 5′ and 3′ ends compatible with the restriction sites NdeI and XhoI in the plasmid pET24d-ELP1-90 (FIG. 1). This plasmid was digested with the restriction enzymes NdeI and XhoI and the annealed DNA sequence was ligated into the cut vector. Insertion was confirmed by restriction digest and DNA sequencing. The resulting plasmid was designated as pET24d-Ex-4 ELP1-90 (FIG. 2A), and the sequence of the resulting Exendin-4-ELP fusion shown in FIG. 2B. Primers for construction of the fusion are also indicated.

pET24d-Ex-4 ELP1-90 was used to transform the E. coli strain BRL (Invitrogen) and selected transformants were grown in media 3 (1.2% Tryptone Peptone, 2.4% yeast extract, 5 g/L casamino acids, 2% glycerol, 2.313 g Potassium phosphate dibasic/L, 12.541 g Potassium phosphate monobasic/L) in shake flasks. Production proceeded by autoinduction by inoculating 1 OD cells into 1 L of media 3 and allowing growth to proceed for 17 hr at 37° C. without addition of inducer. The product was recovered by collection of the cell pellet, sonicated to disrupt the cells and recovered by thermal and/or salt induced transition modulated by the ELP moiety (Improved Non-chromatographic Purification of a Recombinant Protein by Cationic Elastin-like Polypeptides, Dong Woo Lim, Kimberly Trabbic-Carlson, J. Andrew MacKay, and Ashutosh Chilkoti. Biomacromolecules 2007, 8, 1417-1424).

This example is with the ELP designated 1-90. This is based on the VPGXG (SEQ ID NO: 3) motif where X is a V, G or A in the ratio 5:3:2 in a 10 unit repeat, repeated 8× with a final (C-terminal) 10-unit repeat where X is a V, G, A and Win the ratio 4:3:2:1.

[(VPGXG)10]₉ where the X residue in the ten sequential iterations of the repeat unit (numerical subscript) can be described as [(V_(1, 4, 5, 6, 10)G_(2, 7, 9)A_(3, 8))₈ (V_(1, 4, 5, 6)G_(2, 7, 9)A_(3, 8) W₁₀)].

The ELP may be any combination of VPGXG (SEQ ID NO: 3) units where X is any of the 20 natural amino, acids, except proline, in any combination of repeat units of any length. In addition, the amino acid may be an unnatural amino acid for which the host strain has been engineered to accept an engineered tRNA for incorporation at specific codon (Wang L, Brock A, Herberich B, Schultz P G. Expanding the genetic code of Escherichia coli. [2001] Science 292, 498-500).

This construct was produced in the cytosol with an N-terminal methionine, which is normally removed by methionine aminopeptidase. Complete and accurate processing of the methionine, however, cannot be assumed; this enzyme may also remove the N-terminal histidine of the Exendin-4 moiety. This could result in a mixture of, unprocessed, processed and incorrectly processed products. Consequently, further constructs were developed to generate products with correctly processed N-termini.

Primers were designed to add a Tev protease (Tobacco Etch Virus cysteine protease) cleavage site between the N-terminal methionine and the histidine at the N-terminus of Exendin-4. This allows for removal of the methionine and the Tev recognition sequence to give the mature N-terminus of Exendin-4 (histidine). This can be done post-production or the Tev protease can be co-expressed to cleave the recognition sequence during production, for instance, as an intein (Ge, X., Yang, D. S. C., Trabbic-Carlson, K., Kim, B., Chilkoti, A. and Filipe, C. D. M. Self-Cleavable Stimulus Responsive Tags for Protein Purification without Chromatography. J. Am. Chem. Soc. 127, 11228-11229, 2005). The Tev Exendin-4 sequence is shown in FIG. 3A. FIG. 3B shows additional sequences added, labeled as “Linker Tev,” provide a better target for the Tev protease.

An alternative route to obtaining a correctly processed N-terminus for Ex-4 is to use a leader or signal sequence that directs the product to the periplasm and which is cleaved by a signal peptidase in the process. In this instance, a signal sequence, DsbA, that directs the transcript to the signal recognition particle for direct secretion of the polypeptide into the periplasm is given. (See FIG. 4A). The plasmid pET24d-DsbA-Ex-4 ELP1-90 is shown in FIG. 4B.

While this example illustrates the preparation of therapeutic agents with Exendin-4 sequences, such sequences can be replaced with GLP-1, insulin, Factor VII/VIIa, or other therapeutic protein listed in Table 1, generated in exactly or a similar manner as detailed for Exendin-4.

Example 6 GLP1-ELP Fusion Protein

The ELP plasmid constructs were used to prepare two GLP1-ELP fusion proteins, GLP1(A8G,7-37)ELP1-90 and GLP1(A8G,7-37)ELP1-120. The plasmid contructs, fusion-encoding nucleotide sequence, as well as the amino acid sequence of the resulting fusion proteins are shown in FIGS. 5 and 6.

Both constructs contain an N-terminal Tev protease site to allow processing to the mature form where His⁷ of GLP1 is at the N-terminus. The processed fusion proteins have calculated molecular weights of about 39,536 and about 50,828, respectively.

Example 7 FVII ELP Fusion Protein

The coagulation factor VII (FVII) gene was modified by PCR from a cDNA clone (Oragene) to add restriction sites at the 5′ and 3′ ends for cloning into the ELP-containing vector. At the 5′ end an NheI site was added and at the 3′ end a NotI site was added. The DNA and amino acid sequences of the Factor VII gene are shown in the accompanying Sequence Listing as SEQ ID NOS: 34 and 33, respectively. The DNA sequences of the 5′ and 3′ primers used to PCR amplify the factor VII (FVII) gene were:

(SEQ ID NO.: 49) P13: CTAGCTAGCATGGTCTCCCAGGCCCTC (SEQ ID NO.: 50) P14: TATTCTTGCGGCCGCGGGAAATGGGGCTCGCAG

The resulting PCR fragment was digested with the restriction enzymes NheI and NotI and ligated into the plasmid pcDNA3.1+ELP1-90 previously digested with the restriction enzymes NheI and NotI (FIG. 7A).

The resulting plasmid, pcDNA3.1+FVII-ELP1-90, was transiently transfected into HEK293 cells and culture media harvested. The ELP fusion was purified by phase transition (FIGS. 9 and 10).

The nucleotide and amino acid sequences of the FactorVII-ELP fusion is shown in FIG. 7B. As shown, the FactorVII-ELP fusion protein contains a Tev protease linker between the FactorVII component and the ELP component. This linker is optional.

Example 8 Insulin ELP Fusion Protein

The cDNA for the human insulin gene is modified at the 5′ and 3′ ends for insertion in to pET24d-ELP1-90. The 5′ primer adds an N-terminal methionine for bacterial expression and an NdeI restriction enzyme site. The 3′ primer adds an XhoI restriction enzyme site. The PCR product and the plasmid are both digested with the restriction enzymes NdeI and XhoI and ligated together. The sequence of the insulin (Chains B, C, and A fused to ELP1 is shown in FIG. 8A.

Correct insertion is determined by restriction digest and DNA sequencing. The resulting plasmid, designated pET24d Insulin-ELP1-90, is shown in FIG. 8B.

The native insulin form is generated after recovery from E. coli by treatment with trypsin and carboxypeptidase B to remove the C-peptide chain.

For correct processing of the N-terminus of the B-chain similar modifications to those made for the Exendin-4 fusion (protease cleavage site, signal sequence) can be implemented (see Example 4). Alternatively, the first two residues can be Met-Arg, which can also be removed by trypsin digestion in production of the final material (R. M. Belagaje, S. G. Reams, S. C. Ly and W. F. Prouty, Increased production of low molecular weight recombinant proteins in Escherichia coli. Protein Sci. 6, 1953-1962, 1997).

Additional constructs would place the insulin cDNA at the 3′ end of the ELP for a C-terminal fusion, add linkers between the Insulin and ELP sequences, and/or use modified forms of insulin which have no C-peptide (single chain insulins as described) removing the need for additional processing.

Example 9 Synthesis of the ELP Gene for Conjugation

A gene encoding a 50 amino acid sequence was constructed from chemically-synthesized oligonucleotides using standard molecular biology protocols. The 50 amino acid sequence contained 10 repeats of the pentapeptide VPGXG (SEQ ID NO: 3), where the guest residues (V, G, and A in a 5:3:2 molar ratio) were selected to provide a Tt of 40° C. The gene was oligomerized end-to-end by standard molecular biology techniques, to produce an oligomeric ELP gene. Additionally a single 50 amino acid sequence was constructed containing the 10 repeat pentapeptide VPGXG (SEQ ID NO: 3) polypeptide where the guest residues were V, G, A and C in a 4:3:2:1 molar ratio. This sequence could be added at any cycle of the oligomerization process to introduce a single cysteine residue into the final construct at a chosen point along the length of the construct.

The example given here is with the ELP designated 1-90. This is based on the VPGXG (SEQ ID NO: 3) motif where X is a V, G or A in the ratio 5:3:2 in a 10-unit repeat, repeated 8× with a final (C-terminal) 10-unit repeat where X is a V, G, A and C in the ratio 4:3:2:1, i.e., [(VPGXG)10] (SEQ ID NO.: 3).

Alternatively, the residue could be one of either arginine, lysine, aspartic acid or glutamic acid. The purpose of these amino acids is to provide a reactive side chain for the chemical conjugation of, for example, insulin. In this particular case the use of an ELP would be to extend the circulating half-life of the therapeutic protein (e.g., insulin) to provide prolonged basal glucose control. Conjugated to an ELP that transitions at body temperature, the insulin would form a precipitated depot at the site of injection in a similar manner to Lantus® (Sanofi Aventis) but without the requirement for formulation in acidic (pH 4.0) conditions with m-cresol for a more tolerable injection.

Example 10 Potency and Half-Life of Factor VII-ELP

FIG. 11 shows the activation of Factor X by FactorVIIa-ELP1-90, and by Factor VIIa as a comparison. Factor VII-ELP was produced in HEK cells. Factor VIIa was derived from human plasma. As shown, FactorVIIa-ELP retains full activity.

When administered to rats by i.v., Factor VII-ELP demonstrated a half-life of about 690 minutes. In contrast, Factor VII demonstrated a half-life of 45-60 minutes. Half-life in this example was measured by sandwich ELISA for FactorVII. FIG. 12.

Also in contrast, the reported half-life for NovoSeven™ is 45 minutes, the reported half-life for FactorVIIa-albumin fusion is 263 minutes, and the reported half-life for Factor VIIa-PEG is 300 minutes in mice and 600 minutes in dog.

Example 11 GLP-1 (or Exendin-4) In Vitro Bioassay

Activation of the GLP-1 receptor (GLP1R) results in production of cAMP secondary messenger within the cell. Therefore, GLP-1 or Exendin-4 analogs and corresponding therapeutic agents may be tested by their ability to activate GLP1R on the cell surface and produce cAMP.

For this bioassay CHO cells transfected with cDNA coding for GLP1R are used. These cells respond to stimulation by GLP-1 and produce high levels of cAMP. Log phase growing cells are plated and increasing concentrations of test compounds (e.g., therapeutic agent of the invention, or GLP-1 or exendin-4 functional analog) are added to the cells. After an appropriate incubation period (usually 15-60 min) in physiological buffer at 37° C. the cAMP produced is measured using a CatchPoint cAMP assay kit from Molecular Devices (Sunnyvale, Calif.). The EC₅₀ of each test compound as compared to GLP-1 peptide or Exendin-4 peptide (or as compared to an unfused or unconjugated counterpart of a therapeutic agent of the invention) is indicative of the changes in activity due to a specific modifications introduced into the peptide, or due to particular chemical or recombinant coupling to an ELP component.

As shown in FIG. 13, both GLP1-ELP(PB0868) and Exendin-4-ELP(PB 0859) maintain high activity in vitro, shown in comparison to Exendin alone. It is of note that the specific activity of Albugon® and Liraglutide® run 50-100 fold less than the exendin peptide.

Example 12 GLP-1 (or Exendin-4) In Vivo Bioassay

The activity of GLP-1 or Exendin analogues or corresponding therapeutic agents may be tested in animals. For this assay, normal or diabetic animals may be used. Diabetic animals with blood glucose concentration 300-500 mg/dl are injected with different doses of GLP-1 or Exendin analogues or corresponding therapeutic agent, and changes in blood glucose monitored with a glucometer. The drop in glucose at different times points post administration is compared to that resulting with standard amounts of GLP-1 or Exendin-4 peptide, or compared to an unfused or unconjugated counterpart of a therapeutic agent of the invention. Alternatively, the blood glucose excursion in normal or diabetic animals during specific time period after administration of exogenous glucose is compared to GLP-1 or Exendin-4 (or to unfused or unconjugated counterparts of therapeutic agents). In this way the activity of the analogues and fusion proteins can be compared to the natural peptides.

FIG. 14 shows the pharmacokinetics of GLP1-ELP1-120 in rats administered both by i.v. and subcutaneously. Three rats were used for each time point. The dose was ˜10 mg/kg. The T_(1/2) when administered by i.v. was about 12.9 hours. The T_(1/2) when administered subcutaneously was about 8.6 hours.

FIG. 15 shows the pharmacokinetics of GLP1-ELP1-120 in rabbits administered both by i.v. and subcutaneously. Three rabbits were used for each time point. The dose was ˜1 mg/kg. The T_(1/2) when administered by i.v. was about 20 hours. The T_(1/2) when administered subcutaneously was about 24 hours.

FIG. 16 shows the sustained glycemic control in diabetic mice with GLP1-ELP1-90.

All reference cited herein are hereby incorporated by reference in their entireties. While the invention has been has been described herein in reference to specific aspects, features and illustrative embodiments of the invention, it will be appreciated that the utility of the invention is not thus limited, but rather extends to and encompasses numerous other variations, modifications and alternative embodiments, as will suggest themselves to those of ordinary skill in the field of the present invention, based on the disclosure herein. 

1. A pharmaceutical composition comprising an effective amount of a fusion construct, the fusion construct comprising, a plurality of elastic peptide components of the formula (VPGXG)₁₅₋₁₅₀, where X is an independently selected amino acid, and a plurality of target molecule-binding segments.
 2. The composition of claim 1, wherein at least one target molecule-binding segment targets a cell type.
 3. The composition of claim 2, wherein the cell type is a cancer cell.
 4. The composition of claim 1, wherein the composition is for systemic administration.
 5. The composition of claim 1, wherein X is independently selected from Val, Ile, Leu, Ala, Gly, and Trp.
 6. The composition of claim 1, wherein the fusion construct has a transition temperature of between 35 and 60° C.
 7. The composition of claim 6, wherein the fusion construct has a transition temperature of from 38 to 45° C.
 8. The composition of claim 1, wherein the fusion construct has a transition temperature of less than 37° C. 